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1
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Isogai T, Hirosawa KM, Kanno M, Sho A, Kasai RS, Komura N, Ando H, Furukawa K, Ohmi Y, Furukawa K, Yokota Y, Suzuki KG. Extracellular vesicles adhere to cells primarily by interactions of integrins and GM1 with laminin. J Cell Biol 2025; 224:e202404064. [PMID: 40304687 PMCID: PMC12042775 DOI: 10.1083/jcb.202404064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 12/09/2024] [Accepted: 03/11/2025] [Indexed: 05/02/2025] Open
Abstract
Tumor-derived extracellular vesicles (EVs) have attracted significant attention, yet the molecular mechanisms that govern their specific binding to recipient cells remain elusive. Our in vitro study utilizing single-particle tracking demonstrated that integrin heterodimers comprising α6β4 and α6β1 and ganglioside, GM1, are responsible for the binding of small EV (sEV) subtypes to laminin. EVs derived from four distinct tumor cell lines, regardless of size, exhibited high binding affinities for laminin but not for fibronectin, although fibronectin receptors are abundant in EVs and have functional roles in EV-secreting cells. Our findings revealed that integrins in EVs bind to laminin via the conventional molecular interface, facilitated by CD151 rather than by inside-out signaling of talin-1 and kindlin-2. Super-resolution movie observation revealed that sEV integrins bind only to laminin on living recipient cells. Furthermore, sEVs bound to HUVEC and induced cell branching morphogenesis in a laminin-dependent manner. Thus, we demonstrated that EVs predominantly bind to laminin on recipient cells, which is indispensable for cell responses.
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Affiliation(s)
- Tatsuki Isogai
- The United Graduate School of Agricultural Science, Gifu University, Gifu, Japan
| | | | - Miki Kanno
- Graduate School of Natural Science and Technology, Gifu University, Gifu, Japan
| | - Ayano Sho
- Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Rinshi S. Kasai
- Division of Advanced Bioimaging, National Cancer Center Research Institute (NCCRI), Tokyo, Japan
| | - Naoko Komura
- Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan
| | - Hiromune Ando
- The United Graduate School of Agricultural Science, Gifu University, Gifu, Japan
- Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan
- Graduate School of Natural Science and Technology, Gifu University, Gifu, Japan
- Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
- Innovation Research Center for Quantum Medicine, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Keiko Furukawa
- Department of Biomedical Sciences, Chubu University, Kasugai, Japan
| | - Yuhsuke Ohmi
- Department of Biomedical Sciences, Chubu University, Kasugai, Japan
| | - Koichi Furukawa
- Department of Biomedical Sciences, Chubu University, Kasugai, Japan
| | - Yasunari Yokota
- Department of Information Science, Faculty of Engineering, Gifu University, Gifu, Japan
| | - Kenichi G.N. Suzuki
- The United Graduate School of Agricultural Science, Gifu University, Gifu, Japan
- Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan
- Graduate School of Natural Science and Technology, Gifu University, Gifu, Japan
- Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
- Division of Advanced Bioimaging, National Cancer Center Research Institute (NCCRI), Tokyo, Japan
- Innovation Research Center for Quantum Medicine, Graduate School of Medicine, Gifu University, Gifu, Japan
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Rubinstein E, Théry C, Zimmermann P. Tetraspanins affect membrane structures and the trafficking of molecular partners: what impact on extracellular vesicles? Biochem Soc Trans 2025; 0:BST20240523. [PMID: 40135387 DOI: 10.1042/bst20240523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 03/03/2025] [Accepted: 03/07/2025] [Indexed: 03/27/2025]
Abstract
Tetraspanins are a family of 33 proteins in mammals believed to play a crucial role in the compartmentalization of various associated proteins within cells and membranes. Recent studies have elucidated the structure of several tetraspanin members, revealing that while the four transmembrane domains typically adopt a cone-shaped configuration in crystals, other conformations are also possible. This cone-shaped structure may explain why tetraspanins are often enriched in curved and tubular cellular structures, such as microvilli, tunneling nanotubes, retraction fibers, or at the site of virus budding, and may contribute to the formation or maintenance of these structures. Tetraspanins have also been detected on midbody remnants and migrasomes, as well as on extracellular vesicles (EVs), for which CD9, CD81, and CD63 are widely used as markers. Although their impact on certain membrane structures and their ability to regulate the function and trafficking of associated proteins would suggest a potential role of tetraspanins either in EV formation or in regulating their protein composition, or both, efforts to characterize these roles have been complicated by conflicting results. In line with the interaction of certain tetraspanins with cholesterol, two recent studies have suggested that the presence or organization of oxysterols and cholesterol in EVs may be regulated by Tspan6 and CD63, respectively, paving the way for further research on the influence of tetraspanins on the lipid composition of EVs.
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Affiliation(s)
- Eric Rubinstein
- Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Sorbonne Université, Inserm, CNRS, Paris, France
| | - Clotilde Théry
- Institut Curie Research Center, PSL Research University, INSERM U932, Paris, France
- Institut Curie Research Center, CurieCoreTech Extracellular Vesicles, Paris, France
| | - Pascale Zimmermann
- Equipe labellisée Ligue 2024, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université, Inserm, CNRS, Institut Paoli-Calmettes, Marseille, France
- Department of Human Genetics, KU Leuven, Leuven, Belgium
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Ramírez-Salinas G, Rosales-Hernandéz MC, Correa-Basurto J, Guerrero-González I, Hernández-Castro SS, Martinez-Archundia M. In silico study suggests potential drugs that target CD151 to treat breast cancer and glioblastoma. J Comput Chem 2024; 45:2666-2677. [PMID: 39082832 DOI: 10.1002/jcc.27439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 02/08/2024] [Accepted: 05/13/2024] [Indexed: 10/11/2024]
Abstract
Recently tetraspanin CD151 has been identified as an important biological target involved in metastatic processes which include cell adhesion, tumor progression processes, and so forth in different types of cancers, such as breast cancer and glioblastoma. This in Silico study considered 1603 compounds from the Food and Drug Administration database, after performing an ADMET analysis; we selected 853 ligands, which were used for docking analysis. The most promising ligands were selected from docking studies, based on two criteria: (a) showed lowest affinity to the CD151 protein and (b) they interact with the QRD motif, located in the second extracellular loop. Furthermore, we investigate the stability of the protein-ligand complexes through MD simulations as well as free energy MM-PBSA calculations. From these results, loperamide and glipizide were identified as the best evaluated drugs. We suggest an in vitro analysis is needed to confirm our in silico prediction studies.
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Affiliation(s)
- Gema Ramírez-Salinas
- Laboratory for the Design and Development of New Drugs and Biotechnological. Innovation, SEPI-Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Martha Cecilia Rosales-Hernandéz
- Laboratorio de Biofísica y Biocatálisis, Sección de estudios de Posgrado e Investigación Escuela superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - José Correa-Basurto
- Laboratory for the Design and Development of New Drugs and Biotechnological. Innovation, SEPI-Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Issac Guerrero-González
- Laboratorio de Biofísica y Biocatálisis, Sección de estudios de Posgrado e Investigación Escuela superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Selene Saraí Hernández-Castro
- Laboratory for the Design and Development of New Drugs and Biotechnological. Innovation, SEPI-Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Marlet Martinez-Archundia
- Laboratory for the Design and Development of New Drugs and Biotechnological. Innovation, SEPI-Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
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Chen J, Ding Y, Jiang C, Qu R, Wren JD, Georgescu C, Wang X, Reuter DN, Liu B, Giles CB, Mayr CH, Schiller HB, Dai J, Stipp CS, Subramaniyan B, Wang J, Zuo H, Huang C, Fung KM, Rice HC, Sonnenberg A, Wu D, Walters MS, Zhao YY, Kanie T, Hays FA, Papin JF, Wang DW, Zhang XA. CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation. Circ Res 2024; 134:1330-1347. [PMID: 38557119 PMCID: PMC11081830 DOI: 10.1161/circresaha.123.323190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 03/19/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3 (interferon-induced transmembrane protein 3), which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase. CONCLUSIONS Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.
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Affiliation(s)
- Junxiong Chen
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Yingjun Ding
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Chao Jiang
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Rongmei Qu
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | | | | | - Xuejun Wang
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | | | - Beibei Liu
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Cory B. Giles
- Oklahoma Medical Research Foundation, Oklahoma City, USA
| | | | | | - Jingxing Dai
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | | | | | - Jie Wang
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Houjuan Zuo
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Chao Huang
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Kar-Ming Fung
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Heather C. Rice
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | | | - David Wu
- University of Chicago, Chicago, IL, USA
| | | | - You-Yang Zhao
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
- Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Tomoharu Kanie
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Franklin A. Hays
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - James F. Papin
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Dao Wen Wang
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Xin A. Zhang
- University of Oklahoma Health Sciences Center, Oklahoma City, USA
- Lead contact
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5
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Zhu Y, Saint-Pol J, Nguyen V, Rubinstein E, Boucheix C, Greco C. The Tetraspanin Tspan8 Associates with Endothelin Converting Enzyme ECE1 and Regulates Its Activity. Cancers (Basel) 2023; 15:4751. [PMID: 37835445 PMCID: PMC10571763 DOI: 10.3390/cancers15194751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/20/2023] [Accepted: 09/22/2023] [Indexed: 10/15/2023] Open
Abstract
Tspan8 is a member of the tetraspanins family of cell surface molecules. The ability of tetraspanins to organize membrane microdomains with other membrane molecules and interfere with their function suggests that they could act as surface integrators of external or internal signals. Among the first identified tetraspanins, Tspan8 promotes tumor progression and metastasis, presumably by stimulating angiogenesis and cell motility. In patients, its expression on digestive tract tumors seems to be associated with a bad prognosis. We showed previously that Tspan8 associates with E-cadherin and EGFR and modulates their effects on cell motility. Using Mass spectrometry and western blot, we found a new partner, the endothelin converting enzyme ECE1, and showed that Tspan8 amplifies its activity of conversion of the endothelin-1 precursor bigET1 to endothelin. This was observed by transduction of the colon carcinoma cell line Isreco1, which does not express Tspan8, and on ileum tissue fragments of tspan8ko mice versus wild type mice. Given these results, Tspan8 appears to be a modulator of the endothelin axis, which could possibly be targeted in case of over-activity of endothelins in biological processes of tissues expressing Tspan8.
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Affiliation(s)
- Yingying Zhu
- UMR-S 1004, SFR André Lwoff, Inserm, 94800 Villejuif, France; (Y.Z.); (J.S.-P.); (E.R.)
- Université Paris Saclay, 91190 Gif-sur-Yvette, France;
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Julien Saint-Pol
- UMR-S 1004, SFR André Lwoff, Inserm, 94800 Villejuif, France; (Y.Z.); (J.S.-P.); (E.R.)
- Université Artois, UR 2465, Blood-Brain Barrier Laboratory (LBHE), 62300 Lens, France
| | - Viet Nguyen
- Université Paris Saclay, 91190 Gif-sur-Yvette, France;
- Plateforme Spectrométrie de Masse, Laboratoire Biochimie-Hormonologie, Hôpital Robert-Debré, Assistance Publique Hôpitaux de Paris (APHP), 75610 Paris, France
| | - Eric Rubinstein
- UMR-S 1004, SFR André Lwoff, Inserm, 94800 Villejuif, France; (Y.Z.); (J.S.-P.); (E.R.)
- Centre d’Immunologie et des Maladies Infectieuses, Inserm, CNRS, Sorbonne Université, CIMI-Paris, 75013 Paris, France
| | - Claude Boucheix
- Université Paris Saclay, 91190 Gif-sur-Yvette, France;
- UMR-S 1197, SFR André Lwoff, Inserm, 94800 Villejuif, France
| | - Céline Greco
- Department of Pain and Palliative Care, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (APHP), 75610 Paris, France
- U1163, IMAGINE Institute, Université de Paris Cité, Inserm, 75014 Paris, France
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6
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Todorova VK, Byrum SD, Mackintosh SG, Jamshidi-Parsian A, Gies AJ, Washam CL, Jenkins SV, Spiva T, Bowman E, Reyna NS, Griffin RJ, Makhoul I. Exosomal MicroRNA and Protein Profiles of Hepatitis B Virus-Related Hepatocellular Carcinoma Cells. Int J Mol Sci 2023; 24:13098. [PMID: 37685904 PMCID: PMC10487651 DOI: 10.3390/ijms241713098] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/14/2023] [Accepted: 08/18/2023] [Indexed: 09/10/2023] Open
Abstract
Infection with hepatitis B virus (HBV) is a main risk factor for hepatocellular carcinoma (HCC). Extracellular vesicles, such as exosomes, play an important role in tumor development and metastasis, including regulation of HBV-related HCC. In this study, we have characterized exosome microRNA and proteins released in vitro from hepatitis B virus (HBV)-related HCC cell lines SNU-423 and SNU-182 and immortalized normal hepatocyte cell lines (THLE2 and THLE3) using microRNA sequencing and mass spectrometry. Bioinformatics, including functional enrichment and network analysis, combined with survival analysis using data related to HCC in The Cancer Genome Atlas (TCGA) database, were applied to examine the prognostic significance of the results. More than 40 microRNAs and 200 proteins were significantly dysregulated (p < 0.05) in the exosomes released from HCC cells in comparison with the normal liver cells. The functional analysis of the differentially expressed exosomal miRNAs (i.e., mir-483, mir-133a, mir-34a, mir-155, mir-183, mir-182), their predicted targets, and exosomal differentially expressed proteins (i.e., POSTN, STAM, EXOC8, SNX9, COL1A2, IDH1, FN1) showed correlation with pathways associated with HBV, virus activity and invasion, exosome formation and adhesion, and exogenous protein binding. The results from this study may help in our understanding of the role of HBV infection in the development of HCC and in the development of new targets for treatment or non-invasive predictive biomarkers of HCC.
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Affiliation(s)
- Valentina K. Todorova
- Department of Internal Medicine/Division of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Stephanie D. Byrum
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (S.D.B.); (S.G.M.); (A.J.G.); (C.L.W.)
| | - Samuel G. Mackintosh
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (S.D.B.); (S.G.M.); (A.J.G.); (C.L.W.)
| | - Azemat Jamshidi-Parsian
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (A.J.-P.); (S.V.J.); (R.J.G.)
| | - Allen J. Gies
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (S.D.B.); (S.G.M.); (A.J.G.); (C.L.W.)
| | - Charity L. Washam
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (S.D.B.); (S.G.M.); (A.J.G.); (C.L.W.)
| | - Samir V. Jenkins
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (A.J.-P.); (S.V.J.); (R.J.G.)
| | - Timothy Spiva
- Biology Department, Ouachita Baptist University, Arkadelphia, AR 71998, USA; (T.S.); (E.B.); (N.S.R.)
| | - Emily Bowman
- Biology Department, Ouachita Baptist University, Arkadelphia, AR 71998, USA; (T.S.); (E.B.); (N.S.R.)
| | - Nathan S. Reyna
- Biology Department, Ouachita Baptist University, Arkadelphia, AR 71998, USA; (T.S.); (E.B.); (N.S.R.)
| | - Robert J. Griffin
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (A.J.-P.); (S.V.J.); (R.J.G.)
| | - Issam Makhoul
- Department of Internal Medicine/Division of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
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Li YC, Wu Y, Chen G, Zhu LZ, Luo X, Nie QQ, Zhang L, Zuo CJ. Tetraspanins predict the prognosis and characterize the tumor immune microenvironment of glioblastoma. Sci Rep 2023; 13:13317. [PMID: 37587203 PMCID: PMC10432458 DOI: 10.1038/s41598-023-40425-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 08/10/2023] [Indexed: 08/18/2023] Open
Abstract
Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor. Conventional treatments have not achieved breakthroughs in improving survival. Therefore, novel molecular targets and biomarkers need to be identified. As signal transduction docks on the cell membrane, tetraspanins (TSPANs) are associated with various tumors; however, research on their role in GBM remains extremely scarce. Gene expression and clinicopathological characteristic data were obtained from GEPIA, CGGA, HPA, cBioPortal, and GSCA databases to analyze the mRNA and protein expression levels, prognostic value, clinical relevance, mutation status, and targeted drug sensitivity of TSPANs in GBM. Gene set enrichment analysis (GSEA), Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used for biological process enrichment. Data from TCGA and TCIA were used to construct the tumor immune microenvironment landscape of TSPANs. Different R software algorithms were used to analyze the immune score, immune cell infiltration, and immune checkpoint correlation. Univariate and multivariate analyses were performed for TSPAN4, which had the most significant predictive prognostic value, and a nomogram model was constructed to predict individual outcomes. The expression and function of TSPAN4 were verified in vitro. TSPAN3/4/6/11/12/18/23/24/25/26/27/28/29/30/31expressions were significantly upregulated in GBM, and TSPAN3/4/6/11/18/24/25/26/29/30 were strongly correlated with prognosis. The expression of multiple TSPANs significantly correlated with 1p/19q co-deletion status, IDH mutation status, recurrence, age, and tumor grade. GSEA and GO analyses revealed the potential contribution of TSPANs in cell adhesion and migration. Immune correlation analysis revealed that TSPANs are related to the formation of the GBM tumor microenvironment (TME) and may influence immunotherapy outcomes. TSPAN4 is an independent prognostic factor and TSPAN4 knockdown has been demonstrated to strongly inhibit glioma cell proliferation, invasion, and migration in vitro. We comprehensively elaborated the prognostic value and potential role of differentially expressed TSPANs in GBM, including molecules that scientists have previously overlooked. This study provides a novel and comprehensive perspective on the pathological mechanisms of GBM and the future direction of individualized tumor immunotherapy, which may be a critical link between GBM malignant progression and TME remodeling.
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Affiliation(s)
- Yu-Chao Li
- Department of Nuclear Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Yue Wu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Li-Zhi Zhu
- Department of Nuclear Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Xiu Luo
- Department of Nuclear Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Qian-Qian Nie
- Department of Neurology & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Lu Zhang
- Department of Nuclear Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, China.
| | - Chang-Jing Zuo
- Department of Nuclear Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, China
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8
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Zhou Z, Yang Z, Zhou L, Yang M, He S. The versatile roles of testrapanins in cancer from intracellular signaling to cell-cell communication: cell membrane proteins without ligands. Cell Biosci 2023; 13:59. [PMID: 36941633 PMCID: PMC10025802 DOI: 10.1186/s13578-023-00995-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/21/2023] [Indexed: 03/23/2023] Open
Abstract
The tetraspanins (TSPANs) are a family of four-transmembrane proteins with 33 members in mammals. They are variably expressed on the cell surface, various intracellular organelles and vesicles in nearly all cell types. Different from the majority of cell membrane proteins, TSPANs do not have natural ligands. TSPANs typically organize laterally with other membrane proteins to form tetraspanin-enriched microdomains (TEMs) to influence cell adhesion, migration, invasion, survival and induce downstream signaling. Emerging evidence shows that TSPANs can regulate not only cancer cell growth, metastasis, stemness, drug resistance, but also biogenesis of extracellular vesicles (exosomes and migrasomes), and immunomicroenvironment. This review summarizes recent studies that have shown the versatile function of TSPANs in cancer development and progression, or the molecular mechanism of TSPANs. These findings support the potential of TSPANs as novel therapeutic targets against cancer.
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Affiliation(s)
- Zhihang Zhou
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
- Department of Biomedical Sciences, and Tung Biomedical Sciences Center, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong, SAR, People's Republic of China.
| | - Zihan Yang
- Department of Biomedical Sciences, and Tung Biomedical Sciences Center, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong, SAR, People's Republic of China
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Futian Research Institute, Shenzhen, Guangdong, China
| | - Li Zhou
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Biomedical Sciences, and Tung Biomedical Sciences Center, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong, SAR, People's Republic of China
| | - Mengsu Yang
- Department of Biomedical Sciences, and Tung Biomedical Sciences Center, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong, SAR, People's Republic of China
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Futian Research Institute, Shenzhen, Guangdong, China
| | - Song He
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Fischer NG, Aparicio C. Junctional epithelium and hemidesmosomes: Tape and rivets for solving the "percutaneous device dilemma" in dental and other permanent implants. Bioact Mater 2022; 18:178-198. [PMID: 35387164 PMCID: PMC8961425 DOI: 10.1016/j.bioactmat.2022.03.019] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/14/2022] [Accepted: 03/12/2022] [Indexed: 02/06/2023] Open
Abstract
The percutaneous device dilemma describes etiological factors, centered around the disrupted epithelial tissue surrounding non-remodelable devices, that contribute to rampant percutaneous device infection. Natural percutaneous organs, in particular their extracellular matrix mediating the "device"/epithelium interface, serve as exquisite examples to inspire longer lasting long-term percutaneous device design. For example, the tooth's imperviousness to infection is mediated by the epithelium directly surrounding it, the junctional epithelium (JE). The hallmark feature of JE is formation of hemidesmosomes, cell/matrix adhesive structures that attach surrounding oral gingiva to the tooth's enamel through a basement membrane. Here, the authors survey the multifaceted functions of the JE, emphasizing the role of the matrix, with a particular focus on hemidesmosomes and their five main components. The authors highlight the known (and unknown) effects dental implant - as a model percutaneous device - placement has on JE regeneration and synthesize this information for application to other percutaneous devices. The authors conclude with a summary of bioengineering strategies aimed at solving the percutaneous device dilemma and invigorating greater collaboration between clinicians, bioengineers, and matrix biologists.
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Affiliation(s)
- Nicholas G. Fischer
- MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics, University of Minnesota, 16-212 Moos Tower, 515 Delaware St. SE, Minneapolis, MN, 55455, USA
| | - Conrado Aparicio
- MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics, University of Minnesota, 16-212 Moos Tower, 515 Delaware St. SE, Minneapolis, MN, 55455, USA
- Division of Basic Research, Faculty of Odontology, UIC Barcelona – Universitat Internacional de Catalunya, C/. Josep Trueta s/n, 08195, Sant Cugat del Valles, Barcelona, Spain
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), C/. Baldiri Reixac 10-12, 08028, Barcelona, Spain
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10
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Cai S, Deng Y, Peng H, Shen J. Role of Tetraspanins in Hepatocellular Carcinoma. Front Oncol 2021; 11:723341. [PMID: 34540692 PMCID: PMC8446639 DOI: 10.3389/fonc.2021.723341] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/13/2021] [Indexed: 12/27/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is characterized by high prevalence, morbidity, and mortality. Liver cancer is the sixth most common cancer worldwide; and its subtype, HCC, accounts for nearly 80% of cases. HCC progresses rapidly, and to date, there is no efficacious treatment for advanced HCC. Tetraspanins belong to a protein family characterized by four transmembrane domains. Thirty-three known tetraspanins are widely expressed on the surface of most nucleated cells and play important roles in different biological processes. In our review, we summarize the functions of tetraspanins and their underlying mechanism in the life cycle of HCC, from its initiation, progression, and finally to treatment. CD9, TSPAN15, and TSPAN31 can promote HCC cell proliferation or suppress apoptosis. CD63, CD151, and TSPAN8 can also facilitate HCC metastasis, while CD82 serves as a suppressor of metastasis. TSPAN1, TSPAN8, and CD151 act as prognosis indicators and are inversely correlated to the overall survival rate of HCC patients. In addition, we discuss the potential of role of the tetraspanin family proteins as novel therapeutic targets and as an approach to overcome drug resistance, and also provide suggestions for further research.
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Affiliation(s)
- Sicheng Cai
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yue Deng
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiming Peng
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Shen
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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11
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Susa KJ, Rawson S, Kruse AC, Blacklow SC. Cryo-EM structure of the B cell co-receptor CD19 bound to the tetraspanin CD81. Science 2021; 371:300-305. [PMID: 33446559 DOI: 10.1126/science.abd9836] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 12/09/2020] [Indexed: 12/12/2022]
Abstract
Signaling through the CD19-CD81 co-receptor complex, in combination with the B cell receptor, is a critical determinant of B cell development and activation. It is unknown how CD81 engages CD19 to enable co-receptor function. Here, we report a 3.8-angstrom structure of the CD19-CD81 complex bound to a therapeutic antigen-binding fragment, determined by cryo-electron microscopy (cryo-EM). The structure includes both the extracellular domains and the transmembrane helices of the complex, revealing a contact interface between the ectodomains that drives complex formation. Upon binding to CD19, CD81 opens its ectodomain to expose a hydrophobic CD19-binding surface and reorganizes its transmembrane helices to occlude a cholesterol binding pocket present in the apoprotein. Our data reveal the structural basis for CD19-CD81 complex assembly, providing a foundation for rational design of therapies for B cell dysfunction.
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Affiliation(s)
- Katherine J Susa
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Shaun Rawson
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Andrew C Kruse
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
| | - Stephen C Blacklow
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. .,Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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12
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Hayward S, Gachehiladze M, Badr N, Andrijes R, Molostvov G, Paniushkina L, Sopikova B, Slobodová Z, Mgebrishvili G, Sharma N, Horimoto Y, Burg D, Robertson G, Hanby A, Hoar F, Rea D, Eckhardt BL, Ueno NT, Nazarenko I, Long HM, van Laere S, Shaaban AM, Berditchevski F. The CD151-midkine pathway regulates the immune microenvironment in inflammatory breast cancer. J Pathol 2020; 251:63-73. [PMID: 32129471 DOI: 10.1002/path.5415] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 01/27/2020] [Accepted: 02/25/2020] [Indexed: 12/19/2022]
Abstract
The immune microenvironment in inflammatory breast cancer (IBC) is poorly characterised, and molecular and cellular pathways that control accumulation of various immune cells in IBC tissues remain largely unknown. Here, we discovered a novel pathway linking the expression of the tetraspanin protein CD151 in tumour cells with increased accumulation of macrophages in cancerous tissues. It is notable that elevated expression of CD151 and a higher number of tumour-infiltrating macrophages correlated with better patient responses to chemotherapy. Accordingly, CD151-expressing IBC xenografts were characterised by the increased infiltration of macrophages. In vitro migration experiments demonstrated that CD151 stimulates the chemoattractive potential of IBC cells for monocytes via mechanisms involving midkine (a heparin-binding growth factor), integrin α6β1, and production of extracellular vesicles (EVs). Profiling of chemokines secreted by IBC cells demonstrated that CD151 increases production of midkine. Purified midkine specifically stimulated migration of monocytes, but not other immune cells. Further experiments demonstrated that the chemoattractive potential of IBC-derived EVs is blocked by anti-midkine antibodies. These results demonstrate for the first time that changes in the expression of a tetraspanin protein by tumour cells can affect the formation of the immune microenvironment by modulating recruitment of effector cells to cancerous tissues. Therefore, a CD151-midkine pathway can be considered as a novel target for controlled changes of the immune landscape in IBC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Steven Hayward
- Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham, UK
| | - Mariam Gachehiladze
- Department of Clinical and Molecular Pathology, Palacký Univerzity, Olomouc, Czech Republic
| | - Nahla Badr
- Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham, UK.,Department of Pathology, Menoufia University School of Medicine, Menoufia, Egypt
| | - Regina Andrijes
- Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham, UK
| | - Guerman Molostvov
- Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham, UK
| | - Liliia Paniushkina
- Faculty of Medicine, Institute for Infection Prevention and Hospital Epidemiology, Medical Center - University of Freiburg, Freiburg, Germany
| | - Barbora Sopikova
- Department of Clinical and Molecular Pathology, Palacký Univerzity, Olomouc, Czech Republic
| | - Zuzana Slobodová
- Department of Clinical and Molecular Pathology, Palacký Univerzity, Olomouc, Czech Republic
| | - Giorgi Mgebrishvili
- Department of Clinical and Molecular Pathology, Palacký Univerzity, Olomouc, Czech Republic
| | - Nisha Sharma
- Breast Unit, St James Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Yoshiya Horimoto
- Department of Breast Surgical Oncology, Juntendo University School of Medicine, Tokyo, Japan
| | | | | | - Andrew Hanby
- University of Leeds, Leeds Institute of Cancer and Pathology (LICAP) Leeds, Leeds, UK
| | - Fiona Hoar
- Hospital, Sandwell and West Birmingham Hospitals, Department of General and Breast Surgery, Birmingham, UK
| | - Daniel Rea
- Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham, UK
| | - Bedrich L Eckhardt
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia.,Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX, USA
| | - Naoto T Ueno
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX, USA
| | - Irina Nazarenko
- Faculty of Medicine, Institute for Infection Prevention and Hospital Epidemiology, Medical Center - University of Freiburg, Freiburg, Germany.,German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Heather M Long
- Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham, UK
| | - Steven van Laere
- Translational Cancer Research Unit Center for Oncological Research, University Antwerp, Antwerp, Belgium
| | - Abeer M Shaaban
- Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham, UK
| | - Fedor Berditchevski
- Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham, UK
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13
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Jankovicova J, Frolikova M, Palenikova V, Valaskova E, Cerny J, Secova P, Bartokova M, Horovska L, Manaskova-Postlerova P, Antalikova J, Komrskova K. Expression and distribution of CD151 as a partner of alpha6 integrin in male germ cells. Sci Rep 2020; 10:4374. [PMID: 32152440 PMCID: PMC7062741 DOI: 10.1038/s41598-020-61334-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 02/24/2020] [Indexed: 12/22/2022] Open
Abstract
The physiological importance of CD151 tetraspanin is known from somatic cells and its outside-in signalling through integrins was described. In male germ cells, two tetraspanins, CD9 and CD81, are involved in sperm-egg membrane fusion, and similarly to integrins, they occupy characteristic regions. We report here on a newly discovered presence of CD151 in sperm, and present its expression and distribution during spermatogenesis and sperm transition during the acrosome reaction. We traced CD151 gene and protein expression in testicular cell subpopulations, with strong enrichment in spermatogonia and spermatids. The testicular and epididymal localization pattern is designated to the sperm head primary fusion site called the equatorial segment and when compared to the acrosome vesicle status, CD151 was located into the inner acrosomal membrane overlying the nucleus. Moreover, we show CD151 interaction with α6 integrin subunit, which forms a dimer with β4 as a part of cis-protein interactions within sperm prior to gamete fusion. We used mammalian species with distinct sperm morphology and sperm maturation such as mouse and bull and compared the results with human. In conclusion, the delivered findings characterise CD151 as a novel sperm tetraspanin network member and provide knowledge on its physiology in male germ cells.
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Affiliation(s)
- J Jankovicova
- Laboratory of Reproductive Physiology, Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovak Republic
| | - M Frolikova
- Laboratory of Reproductive Biology, Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50, Vestec, Czech Republic
| | - V Palenikova
- Laboratory of Reproductive Biology, Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50, Vestec, Czech Republic.,Department of Biochemistry, Faculty of Science, Charles University, Hlavova 8, 128 40, Prague 2, Czech Republic
| | - E Valaskova
- Laboratory of Reproductive Biology, Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50, Vestec, Czech Republic
| | - J Cerny
- Laboratory of Structural Bioinformatics of Proteins, Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50, Vestec, Czech Republic
| | - P Secova
- Laboratory of Reproductive Physiology, Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovak Republic
| | - M Bartokova
- Laboratory of Reproductive Physiology, Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovak Republic
| | - L Horovska
- Laboratory of Reproductive Physiology, Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovak Republic
| | - P Manaskova-Postlerova
- Laboratory of Reproductive Biology, Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50, Vestec, Czech Republic.,Department of Veterinary Sciences, Faculty of Agrobiology, Food and Natural Resources, University of Life Sciences Prague, Kamycka 129, 165 00, Prague 6, Czech Republic
| | - J Antalikova
- Laboratory of Reproductive Physiology, Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovak Republic.
| | - K Komrskova
- Laboratory of Reproductive Biology, Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50, Vestec, Czech Republic. .,Department of Zoology, Faculty of Science, Charles University, Vinicna 7, 128 44, Prague 2, Czech Republic.
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14
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Purushothaman G, Thiruvenkatam V. High Yield Expression of Recombinant CD151 in E. coli and a Structural Insight into Cholesterol Binding Domain. Mol Biotechnol 2019; 61:905-915. [PMID: 31541430 DOI: 10.1007/s12033-019-00212-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
CD151 is an abundantly expressed eukaryotic transmembrane protein on the cell surface. It is involved in cell adhesion, angiogenesis and signal transduction as well in disease conditions such as cancer and viral infections. However, the molecular mechanism of CD151 activation is poorly understood due to the lack of structural information. By considering the difficulties in expressing the membrane protein in E. coli, herein we introduce the strategic design for the effective expression of recombinant CD151 protein in E. coli with high yield, that would aid for the structural studies. CD151 having four transmembrane domain (TMD's) along with small and a large extracellular loop (LEL) is constructed in parts to enhance the soluble expression of the protein attached with fusion tag. This has led to the high yield of the recombinant CD151 protein in the designed constructs. The recombinant CD151 protein is characterized and confirmed by western blot, CD and Mass peptide fingerprint. The molecular dynamics simulations (MDS) for the full-length CD151 shows conformational changes in the LEL of the protein in the presence and absence of cholesterol and indicate the certainty of closed and open conformation of CD151 based on cholesterol binding. The MDS results have led to the understanding of the possible underlying mechanism for the activation of the CD151 protein.
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Affiliation(s)
- Gayathri Purushothaman
- Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Simkheda, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Vijay Thiruvenkatam
- Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Simkheda, Palaj, Gandhinagar, 382355, Gujarat, India.
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15
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Hwang S, Takimoto T, Hemler ME. Integrin-independent support of cancer drug resistance by tetraspanin CD151. Cell Mol Life Sci 2019; 76:1595-1604. [PMID: 30778617 PMCID: PMC6439156 DOI: 10.1007/s00018-019-03014-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 12/21/2018] [Accepted: 01/15/2019] [Indexed: 12/19/2022]
Abstract
Tetraspanin protein CD151 has typically been studied as binding partner and functional regulator of laminin-binding integrins. However, we show here that CD151 supports anti-cancer drug resistance independent of integrins. CD151 ablation sensitized multiple tumor cell types to several anti-cancer drugs (e.g., gefitinib and camptothecin), thus increasing apoptosis, as seen using cleaved caspase-3, cleaved PARP (poly (ADP-ribose) polymerase), annexin V, and propidium iodide staining assays. Drug sensitization due to CD151 ablation is integrin-independent, because, (1) effects occurred in cells when integrins were unengaged with ligand, (2) integrin ablation (α3 and α6 subunits) did not mimic effects of CD151 ablation, (3) the CD151QRD mutant, with diminished integrin association, and CD151WT (unmutated CD151) similarly reconstituted drug protection, and (4) treatment with anti-cancer drugs selectively upregulated intracellular nonintegrin-associated CD151 (NIA-CD151), consistent with its role in drug resistance. Together, these results suggest that upregulated CD151 expression may support not only typical integrin-dependent functions, but also integrin-independent survival of circulating (and possibly metastatic) cancer cells during anti-cancer drug therapy.
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Affiliation(s)
- Soonyean Hwang
- Department of Cancer Immunology and Virology, Rm SM-520C, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA
| | - Takayuki Takimoto
- Department of Cancer Immunology and Virology, Rm SM-520C, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.,Department of Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical Center 1180 Nagasone-cho, Kita-ku, Sakai, Osaka, 591-8555, Japan
| | - Martin E Hemler
- Department of Cancer Immunology and Virology, Rm SM-520C, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
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16
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Bonnet M, Maisonial-Besset A, Zhu Y, Witkowski T, Roche G, Boucheix C, Greco C, Degoul F. Targeting the Tetraspanins with Monoclonal Antibodies in Oncology: Focus on Tspan8/Co-029. Cancers (Basel) 2019; 11:179. [PMID: 30769765 PMCID: PMC6406856 DOI: 10.3390/cancers11020179] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 01/28/2019] [Accepted: 01/30/2019] [Indexed: 12/12/2022] Open
Abstract
Tetraspanins are exposed at the surface of cellular membranes, which allows for the fixation of cognate antibodies. Developing specific antibodies in conjunction with genetic data would largely contribute to deciphering their biological behavior. In this short review, we summarize the main functions of Tspan8/Co-029 and its role in the biology of tumor cells. Based on data collected from recently reported studies, the possibilities of using antibodies to target Tspan8 in immunotherapy or radioimmunotherapy approaches are also discussed.
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Affiliation(s)
- Mathilde Bonnet
- Université Clermont Auvergne, INSERM1071, Microbes, Intestins, Inflammation et Susceptibilité de l'hôte, 63001 Clermont-Ferrand CEDEX 1, France.
| | - Aurélie Maisonial-Besset
- Université Clermont Auvergne, INSERM U1240, Imagerie Moléculaire et Stratégies Théranostiques, F-63000 Clermont Ferrand, France.
| | - Yingying Zhu
- Université Paris-Sud, INSERM U935, Bâtiment Lavoisier, 14 Avenue Paul-Vaillant-Couturier, F-94800 Villejuif, France.
| | - Tiffany Witkowski
- Université Clermont Auvergne, INSERM U1240, Imagerie Moléculaire et Stratégies Théranostiques, F-63000 Clermont Ferrand, France.
| | - Gwenaëlle Roche
- Université Clermont Auvergne, INSERM1071, Microbes, Intestins, Inflammation et Susceptibilité de l'hôte, 63001 Clermont-Ferrand CEDEX 1, France.
| | - Claude Boucheix
- Université Paris-Sud, INSERM U935, Bâtiment Lavoisier, 14 Avenue Paul-Vaillant-Couturier, F-94800 Villejuif, France.
| | - Céline Greco
- Université Paris-Sud, INSERM U935, Bâtiment Lavoisier, 14 Avenue Paul-Vaillant-Couturier, F-94800 Villejuif, France.
- Department of Pain and Palliative Medicine AP HP, Hôpital Necker, 75015 Paris, France.
| | - Françoise Degoul
- Université Clermont Auvergne, INSERM U1240, Imagerie Moléculaire et Stratégies Théranostiques, F-63000 Clermont Ferrand, France.
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17
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Vicente-Manzanares M, Sánchez-Madrid F. Targeting the integrin interactome in human disease. Curr Opin Cell Biol 2018; 55:17-23. [DOI: 10.1016/j.ceb.2018.05.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/07/2018] [Accepted: 05/14/2018] [Indexed: 12/21/2022]
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18
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Inhibition of Tetraspanin Functions Impairs Human Papillomavirus and Cytomegalovirus Infections. Int J Mol Sci 2018; 19:ijms19103007. [PMID: 30279342 PMCID: PMC6212908 DOI: 10.3390/ijms19103007] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 09/23/2018] [Accepted: 09/27/2018] [Indexed: 12/14/2022] Open
Abstract
Tetraspanins are suggested to regulate the composition of cell membrane components and control intracellular transport, which leaves them vulnerable to utilization by pathogens such as human papillomaviruses (HPV) and cytomegaloviruses (HCMV) to facilitate host cell entry and subsequent infection. In this study, by means of cellular depletion, the cluster of differentiation (CD) tetraspanins CD9, CD63, and CD151 were found to reduce HPV16 infection in HeLa cells by 50 to 80%. Moreover, we tested recombinant proteins or peptides of specific tetraspanin domains on their effect on the most oncogenic HPV type, HPV16, and HCMV. We found that the C-terminal tails of CD63 and CD151 significantly inhibited infections of both HPV16 and HCMV. Although CD9 was newly identified as a key cellular factor for HPV16 infection, the recombinant CD9 C-terminal peptide had no effect on infection. Based on the determined half-maximal inhibitory concentration (IC50), we classified CD63 and CD151 C-terminal peptides as moderate to potent inhibitors of HPV16 infection in HeLa and HaCaT cells, and in EA.hy926, HFF (human foreskin fibroblast) cells, and HEC-LTT (human endothelial cell-large T antigen and telomerase) cells for HCMV, respectively. These results indicate that HPV16 and HCMV share similar cellular requirements for their entry into host cells and reveal the necessity of the cytoplasmic CD151 and CD63 C-termini in virus infections. Furthermore, this highlights the suitability of these peptides for functional investigation of tetraspanin domains and as inhibitors of pathogen infections.
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19
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Zou F, Wang X, Han X, Rothschild G, Zheng SG, Basu U, Sun J. Expression and Function of Tetraspanins and Their Interacting Partners in B Cells. Front Immunol 2018; 9:1606. [PMID: 30072987 PMCID: PMC6058033 DOI: 10.3389/fimmu.2018.01606] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 06/27/2018] [Indexed: 01/26/2023] Open
Abstract
Tetraspanins are transmembrane proteins that modulate multiple diverse biological processes, including signal transduction, cell–cell communication, immunoregulation, tumorigenesis, cell adhesion, migration, and growth and differentiation. Here, we provide a systematic review of the involvement of tetraspanins and their partners in the regulation and function of B cells, including mechanisms associated with antigen presentation, antibody production, cytokine secretion, co-stimulator expression, and immunosuppression. Finally, we direct our focus to the signaling mechanisms, evolutionary conservation aspects, expression, and potential therapeutic strategies that could be based on tetraspanins and their interacting partners.
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Affiliation(s)
- Fagui Zou
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Xu Wang
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Xinxin Han
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Gerson Rothschild
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
| | - Song Guo Zheng
- Department of Medicine, Milton S. Hershey Medical Center at Penn State University, Pennsylvania, PA, United States.,Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-Sen University, Guangzhou, China
| | - Uttiya Basu
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
| | - Jianbo Sun
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
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20
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Zhang J, Wu T, Zhan S, Qiao N, Zhang X, Zhu Y, Yang N, Sun Y, Zhang XA, Bleich D, Han X. TIMP-1 and CD82, a promising combined evaluation marker for PDAC. Oncotarget 2018; 8:6496-6512. [PMID: 28030805 PMCID: PMC5351648 DOI: 10.18632/oncotarget.14133] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 11/11/2016] [Indexed: 11/25/2022] Open
Abstract
Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a widely secreted protein that regulates cell motility, proliferation, and apoptosis. Although it is recognized that TIMP-1-tetraspanin CD63 regulates epithelial cell apoptosis and proliferation, how TIMP-1 controls cell motility is not well understood. In this study, we identify tetraspanin CD82 (also called KAI1) as a component of the promiscuous TIMP-1 interacting protein complex on cell surface of human pancreatic adenocarcinoma cells. CD82 directly binds to TIMP-1 N-terminal region through its large extracellular loop and co-localizes with TIMP-1 in both cancer cell lines and clinical samples. Moreover, CD82 facilitates membrane-bound TIMP-1 endocytosis, which significantly contributes to the anti-migration effect of TIMP-1. CD82 silencing partially eliminates these functions. TIMP-1 and CD82 expression status in patients with pancreatic ductal adenocarcinoma (PDAC) might demonstrate future usefulness as a differentiation marker and give us new insight into tumorigenic metastatic potential.
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Affiliation(s)
- Jiexin Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tijun Wu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Shanshan Zhan
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Nan Qiao
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Xu Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Yunxia Zhu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Nan Yang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Yujie Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Xin A Zhang
- Stephenson Cancer Center and Department of Physiology, University of Oklahoma Health Science Center, Oklahoma, OK, USA
| | - David Bleich
- Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
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21
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Wang Z, Wang C, Zhou Z, Sun M, Zhou C, Chen J, Yin F, Wang H, Lin B, Zuo D, Li S, Feng L, Duan Z, Cai Z, Hua Y. CD151-mediated adhesion is crucial to osteosarcoma pulmonary metastasis. Oncotarget 2018; 7:60623-60638. [PMID: 27556355 PMCID: PMC5312406 DOI: 10.18632/oncotarget.11380] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2015] [Accepted: 07/26/2016] [Indexed: 01/28/2023] Open
Abstract
CD151, a tetraspanin family protein involved in cell-cell and cell-extracellular matrix interaction, is differentially expressed in osteosarcoma cell membranes. Thus, this study aimed to investigate the role of CD151 in osteosarcoma metastasis. We analyzed CD151 expression in patient tissue samples using immunohistochemistry. CD151 expression was also silenced with shRNA in osteosarcoma cells of high metastatic potential, and cell adhesion, migration and invasion were evaluated in vitro and pulmonary metastasis was investigated in vivo. Mediators of cell signaling pathways were also examined following suppression of CD151 expression. Overall survival for patients with low versus high CD151 expression level was 94 vs. 41 months (p=0.0451). CD151 expression in osteosarcoma cells with high metastatic potential was significantly higher than in those with low metastatic potential (p<0.001). shRNA-mediated silencing of CD151 did not influence cell viability or proliferation; however, cell adhesion, migration and invasion were all inhibited (all p<0.001). In mice inoculated with shRNA-transduced osteosarcoma cells, the number and size of lung metastatic lesions were reduced compared to the mice inoculated with control-shRNA transduced cells (p<0.001). In addition, CD151 knockdown significantly reduced Akt, p38, and p65 phosphorylation as well as focal adhesion kinase, integrin β1, p70s6, and p-mTOR levels. Taken together, CD151 induced osteosarcoma metastasis likely by regulating cell function through adhesion signaling. Further studies are necessary to fully explore the diagnostic and prognostic value of determining CD151 expression in osteosarcoma patients.
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Affiliation(s)
- Zhuoying Wang
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Chongren Wang
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Zifei Zhou
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Mengxiong Sun
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Chenghao Zhou
- Shanghai Bone Tumor Institution, Shanghai, 201620, China
| | - Jian Chen
- Shanghai Bone Tumor Institution, Shanghai, 201620, China
| | - Fei Yin
- Shanghai Bone Tumor Institution, Shanghai, 201620, China
| | - Hongsheng Wang
- Shanghai Bone Tumor Institution, Shanghai, 201620, China
| | - Binhui Lin
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Dongqing Zuo
- Shanghai Bone Tumor Institution, Shanghai, 201620, China
| | - Suoyuan Li
- Shanghai Bone Tumor Institution, Shanghai, 201620, China
| | - Lijin Feng
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Zhenfeng Duan
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Zhengdong Cai
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.,Shanghai Bone Tumor Institution, Shanghai, 201620, China
| | - Yingqi Hua
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.,Shanghai Bone Tumor Institution, Shanghai, 201620, China
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22
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Abstract
The glomerular basement membrane (GBM) is a specialized structure with a significant role in maintaining the glomerular filtration barrier. This GBM is formed from the fusion of two basement membranes during development and its function in the filtration barrier is achieved by key extracellular matrix components including type IV collagen, laminins, nidogens, and heparan sulfate proteoglycans. The characteristics of specific matrix isoforms such as laminin-521 (α5β2γ1) and the α3α4α5 chain of type IV collagen are essential for the formation of a mature GBM and the restricted tissue distribution of these isoforms makes the GBM a unique structure. Detailed investigation of the GBM has been driven by the identification of inherited abnormalities in matrix proteins and the need to understand pathogenic mechanisms causing severe glomerular disease. A well-described hereditary GBM disease is Alport syndrome, associated with a progressive glomerular disease, hearing loss, and lens defects due to mutations in the genes COL4A3, COL4A4, or COL4A5. Other proteins associated with inherited diseases of the GBM include laminin β2 in Pierson syndrome and LMX1B in nail patella syndrome. The knowledge of these genetic mutations associated with GBM defects has enhanced our understanding of cell-matrix signaling pathways affected in glomerular disease. This review will address current knowledge of GBM-associated abnormalities and related signaling pathways, as well as discussing the advances toward disease-targeted therapies for patients with glomerular disease.
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Affiliation(s)
- Christine Chew
- Faculty of Biology Medicine and Health, Wellcome Trust Centre for Cell-Matrix Research, Division of Cell Matrix Biology, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
| | - Rachel Lennon
- Faculty of Biology Medicine and Health, Wellcome Trust Centre for Cell-Matrix Research, Division of Cell Matrix Biology, School of Biological Sciences, University of Manchester, Manchester, United Kingdom.,Department of Paediatric Nephrology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
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23
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TSPAN7, effector of actin nucleation required for dendritic cell-mediated transfer of HIV-1 to T cells. Biochem Soc Trans 2017; 45:703-708. [PMID: 28620031 DOI: 10.1042/bst20160439] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 03/15/2017] [Accepted: 03/21/2017] [Indexed: 01/18/2023]
Abstract
Dendritic cells (DCs) have essential roles in early detection of pathogens and activation of both innate and adaptive immune responses. Whereas human DCs are resistant to productive HIV-1 replication, they have a unique ability to take up virus and transmit it efficiently to T lymphocytes. By doing that, HIV-1 may evade, at least in part, the first line of defense of the immune system, exploiting DCs instead to facilitate rapid infection of a large pool of immune cells. While performing an shRNA screen in human primary monocyte-derived DCs, to gain insights into this cell biological process, we discovered the role played by tetraspanin-7 (TSPAN7). This member of the tetraspanin family appears to be a positive regulator of actin nucleation and stabilization, through the ARP2/3 complex. By doing so, TSPAN7 limits HIV-1 endocytosis and maintains viral particles on actin-rich dendrites for an efficient transfer toward T lymphocytes. While studying the function of TSPAN7 in the control of actin nucleation, we also discovered the existence in DCs of two opposing forces at the plasma membrane: actin nucleation, a protrusive force which seems to counterbalance actomyosin contraction.
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24
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Tetraspanins in infections by human cytomegalo- and papillomaviruses. Biochem Soc Trans 2017; 45:489-497. [PMID: 28408489 DOI: 10.1042/bst20160295] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 02/15/2017] [Accepted: 02/16/2017] [Indexed: 12/30/2022]
Abstract
Members of the tetraspanin family have been identified as essential cellular membrane proteins in infectious diseases by nearly all types of pathogens. The present review highlights recently published data on the role of tetraspanin CD151, CD81, and CD63 and their interaction partners in host cell entry by human cytomegalo- and human papillomaviruses. Moreover, we discuss a model for tetraspanin assembly into trafficking platforms at the plasma membrane. These platforms might persist during intracellular viral trafficking.
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25
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Seipold L, Saftig P. The Emerging Role of Tetraspanins in the Proteolytic Processing of the Amyloid Precursor Protein. Front Mol Neurosci 2016; 9:149. [PMID: 28066176 PMCID: PMC5174118 DOI: 10.3389/fnmol.2016.00149] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 12/05/2016] [Indexed: 12/20/2022] Open
Abstract
Tetraspanins are a family of ubiquitously expressed and conserved proteins, which are characterized by four transmembrane domains and the formation of a short and a large extracellular loop (LEL). Through interaction with other tetraspanins and transmembrane proteins such as growth factors, receptors and integrins, tetraspanins build a wide ranging and membrane spanning protein network. Such tetraspanin-enriched microdomains (TEMs) contribute to the formation and stability of functional signaling complexes involved in cell activation, adhesion, motility, differentiation, and malignancy. There is increasing evidence showing that the tetraspanins also regulate the proteolysis of the amyloid precursor protein (APP) by physically interacting with the APP secretases. CD9, CD63, CD81, Tspan12, Tspan15 are among the tetraspanins involved in the intracellular transport and in the stabilization of the gamma secretase complex or ADAM10 as the major APP alpha secretase. They also directly regulate, most likely in concert with other tetraspanins, the proteolytic function of these membrane embedded enzymes. Despite the knowledge about the interaction of tetraspanins with the secretases not much is known about their physiological role, their importance in Alzheimer's Disease and their exact mode of action. This review aims to summarize the current knowledge and open questions regarding the biology of tetraspanins and the understanding how these proteins interact with APP processing pathways. Ultimately, it will be of interest if tetraspanins are suitable targets for future therapeutical approaches.
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Affiliation(s)
- Lisa Seipold
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel (CAU) Kiel, Germany
| | - Paul Saftig
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel (CAU) Kiel, Germany
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26
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Welser-Alves JV, Boroujerdi A, Feltri ML, Milner R. β4 integrin is not essential for localization of hemidesmosome proteins plectin and CD151 in cerebral vessels. Brain Circ 2016; 2:189-196. [PMID: 30276297 PMCID: PMC6126227 DOI: 10.4103/2394-8108.195285] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 08/24/2016] [Accepted: 08/30/2016] [Indexed: 01/04/2023] Open
Abstract
Objective: In the central nervous system (CNS), β4 integrin is predominantly expressed by endothelial cells lining arterioles. As β4 integrin plays an essential role in epithelial tissues, organizing structural proteins into specialized adhesive structures called hemidesmosomes (HD), the aim of this study was to determine whether it plays a similar role in CNS endothelium. Methods: Dual-immunofluorescence was used to examine the relationship between β4 integrin expression and co-expression of the HD proteins plectin and CD151 in frozen sections of mouse brain, both under normoxic (control) conditions and following chronic mild hypoxia. The requirement of β4 integrin for the localization of HD proteins was examined in transgenic mice lacking β4 integrin expression specifically in endothelial cells (β4-EC-KO mice). Results: Immunofluorescence revealed that in the normal adult CNS, plectin and CD151 strongly co-localized with β4 integrin in arterioles. However, in the chronic mild hypoxia model, in which extensive cerebrovascular remodeling is observed, plectin and CD151 were strongly upregulated on all cerebral vessels, but surprisingly, in capillaries, this occurred in a β4 integrin-independent manner. Unexpectedly, absence of endothelial β4 integrin (in β4-EC-KO mice) had no impact on the expression level or distribution pattern of plectin and CD151 within stable or remodeling cerebral vessels. Conclusions: These results demonstrate that the HD proteins plectin and CD151 are closely associated with β4 integrin on arterioles in normal brain, and are strongly upregulated on remodeling blood vessels. However, unlike its described role in the epidermis, β4 integrin is not essential for localization or regulation of expression of plectin and CD151 in cerebral vessels.
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Affiliation(s)
- Jennifer V Welser-Alves
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Amin Boroujerdi
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - M Laura Feltri
- Department of Biochemistry and Neurology, Hunter James Kelly Research Institute, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA
| | - Richard Milner
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
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27
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Abstract
Alport syndrome is the result of mutations in any of three type IV collagen genes, COL4A3, COL4A4, or COL4A5. Because the three collagen chains form heterotrimers, there is an absence of all three proteins in the basement membranes where they are expressed. In the glomerulus, the mature glomerular basement membrane type IV collagen network, normally comprised of two separate networks, α3(IV)/α4(IV)/α5(IV) and α1(IV)/α2(IV), is comprised entirely of collagen α1(IV)/α2. This review addresses the current state of our knowledge regarding the consequence of this change in basement membrane composition, including both the direct, via collagen receptor binding, and indirect, regarding influences on glomerular biomechanics. The state of our current understanding regarding mechanisms of glomerular disease initiation and progression will be examined, as will the current state of the art regarding emergent therapeutic approaches to slow or arrest glomerular disease in Alport patients.
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28
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Cosgrove D, Liu S. Collagen IV diseases: A focus on the glomerular basement membrane in Alport syndrome. Matrix Biol 2016; 57-58:45-54. [PMID: 27576055 DOI: 10.1016/j.matbio.2016.08.005] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 08/05/2016] [Accepted: 08/17/2016] [Indexed: 12/21/2022]
Abstract
Alport syndrome is the result of mutations in any of three type IV collagen genes, COL4A3, COL4A4, or COL4A5. Because the three collagen chains form heterotrimers, there is an absence of all three proteins in the basement membranes where they are expressed. In the glomerulus, the mature glomerular basement membrane type IV collagen network, normally comprised of two separate networks, α3(IV)/α4(IV)/α5(IV) and α1(IV)/α2(IV), is comprised entirely of collagen α1(IV)/α2. This review addresses the current state of our knowledge regarding the consequence of this change in basement membrane composition, including both the direct, via collagen receptor binding, and indirect, regarding influences on glomerular biomechanics. The state of our current understanding regarding mechanisms of glomerular disease initiation and progression will be examined, as will the current state of the art regarding emergent therapeutic approaches to slow or arrest glomerular disease in Alport patients.
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29
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Termini CM, Lidke KA, Gillette JM. Tetraspanin CD82 Regulates the Spatiotemporal Dynamics of PKCα in Acute Myeloid Leukemia. Sci Rep 2016; 6:29859. [PMID: 27417454 PMCID: PMC4945921 DOI: 10.1038/srep29859] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 06/22/2016] [Indexed: 02/08/2023] Open
Abstract
Patients with acute myeloid leukemia (AML) have increased myeloid cells within their bone marrow that exhibit aberrant signaling. Therefore, therapeutic targets that modulate disrupted signaling cascades are of significant interest. In this study, we demonstrate that the tetraspanin membrane scaffold, CD82, regulates protein kinase c alpha (PKCα)-mediated signaling critical for AML progression. Utilizing a palmitoylation mutant form of CD82 with disrupted membrane organization, we find that the CD82 scaffold controls PKCα expression and activation. Combining single molecule and ensemble imaging measurements, we determine that CD82 stabilizes PKCα activation at the membrane and regulates the size of PKCα membrane clusters. Further evaluation of downstream effector signaling identified robust and sustained activation of ERK1/2 upon CD82 overexpression that results in enhanced AML colony formation. Together, these data propose a mechanism where CD82 membrane organization regulates sustained PKCα signaling that results in an aggressive leukemia phenotype. These observations suggest that the CD82 scaffold may be a potential therapeutic target for attenuating aberrant signal transduction in AML.
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Affiliation(s)
- Christina M Termini
- Department of Pathology, University of New Mexico Health Sciences Center, University of New Mexico, MSC 08-4640, Albuquerque, NM 87131, USA
| | - Keith A Lidke
- Department of Physics and Astronomy, University of New Mexico, MSC 07-4220, Albuquerque, NM 87131, USA
| | - Jennifer M Gillette
- Department of Pathology, University of New Mexico Health Sciences Center, University of New Mexico, MSC 08-4640, Albuquerque, NM 87131, USA
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30
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Matthews AL, Noy PJ, Reyat JS, Tomlinson MG. Regulation of A disintegrin and metalloproteinase (ADAM) family sheddases ADAM10 and ADAM17: The emerging role of tetraspanins and rhomboids. Platelets 2016; 28:333-341. [PMID: 27256961 PMCID: PMC5490636 DOI: 10.1080/09537104.2016.1184751] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are ubiquitous transmembrane “molecular scissors” which proteolytically cleave, or shed, the extracellular regions of other transmembrane proteins. ADAM10 is essential for development because it cleaves Notch proteins to induce Notch signaling and regulate cell fate decisions. ADAM17 is regarded as a first line of defense against injury and infection, by releasing tumor necrosis factor α (TNFα) to promote inflammation and epidermal growth factor (EGF) receptor ligands to maintain epidermal barrier function. However, the regulation of ADAM10 and ADAM17 trafficking and activation are not fully understood. This review will describe how the TspanC8 subgroup of tetraspanins (Tspan5, 10, 14, 15, 17, and 33) and the iRhom subgroup of protease-inactive rhomboids (iRhom1 and 2) have emerged as important regulators of ADAM10 and ADAM17, respectively. In particular, they are required for the enzymatic maturation and trafficking to the cell surface of the ADAMs, and there is evidence that different TspanC8s and iRhoms target the ADAMs to distinct substrates. The TspanC8s and iRhoms have not been studied functionally on platelets. On these cells, ADAM10 is the principal sheddase for the platelet collagen receptor GPVI, and the regulatory TspanC8s are Tspan14, 15, and 33, as determined from proteomic data. Platelet ADAM17 is the sheddase for the von Willebrand factor (vWF) receptor GPIb, and iRhom2 is the only iRhom that is expressed. Induced shedding of either GPVI or GPIb has therapeutic potential, since inhibition of either receptor is regarded as a promising anti-thrombotic therapy. Targeting of Tspan14, 15, or 33 to activate platelet ADAM10, or iRhom2 to activate ADAM17, may enable such an approach to be realized, without the toxic side effects of activating the ADAMs on every cell in the body.
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Affiliation(s)
- Alexandra L Matthews
- a School of Biosciences, College of Life and Environmental Sciences, University of Birmingham , Birmingham , UK
| | - Peter J Noy
- a School of Biosciences, College of Life and Environmental Sciences, University of Birmingham , Birmingham , UK
| | - Jasmeet S Reyat
- a School of Biosciences, College of Life and Environmental Sciences, University of Birmingham , Birmingham , UK
| | - Michael G Tomlinson
- a School of Biosciences, College of Life and Environmental Sciences, University of Birmingham , Birmingham , UK
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31
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Masse I, Agaësse G, Berthier-Vergnes O. [Tetraspanins in cutaneous physiopathology]. Med Sci (Paris) 2016; 32:267-73. [PMID: 27011245 DOI: 10.1051/medsci/20163203011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Tetraspanins are transmembrane proteins that interact laterally with each other and with different partners such as integrins, immunoglobulin (Ig)-domain-containing proteins, growth factors and cytokine receptors. Such tetraspanin-partner complexes help to organize dynamic membrane networks called "tetraspanin web", which trigger different signalling pathways. Despite the fact that tetraspanins seem abundantly and widely expressed, their function remained unclear. However, it is well established that they control fundamental cellular processes including cell survival, adhesion, migration, invasion or viral infection, but the underlying molecular mechanisms are not well elucidated. This review focuses on tetraspanins that are expressed in epidermis and the roles they play in normal and pathological conditions, specifically in skin cancer.
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Affiliation(s)
- Ingrid Masse
- Université de Lyon 1, F-69003 Lyon, France - CNRS, UMR5534, centre de génétique et de physiologie moléculaires et cellulaires, 16, rue Raphaël Dubois, Villeurbanne, F-69622, France
| | - Gweltaz Agaësse
- Université de Lyon 1, F-69003 Lyon, France - CNRS, UMR5534, centre de génétique et de physiologie moléculaires et cellulaires, 16, rue Raphaël Dubois, Villeurbanne, F-69622, France
| | - Odile Berthier-Vergnes
- Université de Lyon 1, F-69003 Lyon, France - CNRS, UMR5534, centre de génétique et de physiologie moléculaires et cellulaires, 16, rue Raphaël Dubois, Villeurbanne, F-69622, France
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32
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Toya SP, Wary KK, Mittal M, Li F, Toth PT, Park C, Rehman J, Malik AB. Integrin α6β1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells. Stem Cells 2016; 33:1719-29. [PMID: 25693840 DOI: 10.1002/stem.1974] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 12/25/2014] [Accepted: 01/14/2015] [Indexed: 12/19/2022]
Abstract
Adhesion of embryonic stem cells (ESCs) to the extracellular matrix may influence differentiation potential and cell fate decisions. Here, we investigated the inductive role of binding of integrin α6β1 expressed in mouse (m)ESCs to laminin-1 (LN1) in mediating the differentiation of ESCs to endothelial cells (ECs). We observed that α6β1 binding to LN1 was required for differentiation to ECs. α6β1 functioned by recruiting the adaptor tetraspanin protein CD151, which activated FAK and Akt signaling and mediated the EC lineage-specifying transcription factor Er71. In contrast, association of the ESC-expressed α3β1, another highly expressed LN1 binding integrin, with CD151, prevented α6β1-mediated differentiation. CD151 thus functioned as a bifurcation router to direct ESCs toward ECs when α6β1 associated with CD151, or prevented transition to ECs when α3β1 associated with CD151. These observations were recapitulated in mice in which α6 integrin or CD151 knockdown reduced the expression of Er71-regulated angiogenesis genes and development of blood vessels. Thus, interaction of α6β1 in ESCs with LN1 activates α6β1/CD151 signaling which programs ESCs toward the EC lineage fate.
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Affiliation(s)
- Sophie P Toya
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, USA.,Department of Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA.,The Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Kishore K Wary
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, USA.,The Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Manish Mittal
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, USA.,The Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Fei Li
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, USA.,The Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Peter T Toth
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Changwon Park
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, USA.,The Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Jalees Rehman
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, USA.,Department of Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA.,The Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Asrar B Malik
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, USA.,The Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA
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33
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Wee JL, Schulze KE, Jones EL, Yeung L, Cheng Q, Pereira CF, Costin A, Ramm G, van Spriel AB, Hickey MJ, Wright MD. Tetraspanin CD37 Regulates β2 Integrin-Mediated Adhesion and Migration in Neutrophils. THE JOURNAL OF IMMUNOLOGY 2015; 195:5770-9. [PMID: 26566675 DOI: 10.4049/jimmunol.1402414] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 10/14/2015] [Indexed: 01/13/2023]
Abstract
Deciphering the molecular basis of leukocyte recruitment is critical to the understanding of inflammation. In this study, we investigated the contribution of the tetraspanin CD37 to this key process. CD37-deficient mice showed impaired neutrophil recruitment in a peritonitis model. Intravital microscopic analysis indicated that the absence of CD37 impaired the capacity of leukocytes to follow a CXCL1 chemotactic gradient accurately in the interstitium. Moreover, analysis of CXCL1-induced leukocyte-endothelial cell interactions in postcapillary venules revealed that CXCL1-induced neutrophil adhesion and transmigration were reduced in the absence of CD37, consistent with a reduced capacity to undergo β2 integrin-dependent adhesion. This result was supported by in vitro flow chamber experiments that demonstrated an impairment in adhesion of CD37-deficient neutrophils to the β2 integrin ligand, ICAM-1, despite the normal display of high-affinity β2 integrins. Superresolution microscopic assessment of localization of CD37 and CD18 in ICAM-1-adherent neutrophils demonstrated that these molecules do not significantly cocluster in the cell membrane, arguing against the possibility that CD37 regulates β2 integrin function via a direct molecular interaction. Moreover, CD37 ablation did not affect β2 integrin clustering. In contrast, the absence of CD37 in neutrophils impaired actin polymerization, cell spreading and polarization, dysregulated Rac-1 activation, and accelerated β2 integrin internalization. Together, these data indicate that CD37 promotes neutrophil adhesion and recruitment via the promotion of cytoskeletal function downstream of integrin-mediated adhesion.
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Affiliation(s)
- Janet L Wee
- Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia; Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia
| | - Keith E Schulze
- Monash Micro Imaging, Monash University, Clayton, Victoria 3800, Australia
| | - Eleanor L Jones
- Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia
| | - Louisa Yeung
- Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia; Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia
| | - Qiang Cheng
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia
| | - Candida F Pereira
- Burnet Institute, Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia; and
| | - Adam Costin
- Monash Micro Imaging, Monash University, Clayton, Victoria 3800, Australia
| | - Georg Ramm
- Monash Micro Imaging, Monash University, Clayton, Victoria 3800, Australia
| | - Annemiek B van Spriel
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Michael J Hickey
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia
| | - Mark D Wright
- Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia;
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Yamada M, Sekiguchi K. Molecular Basis of Laminin-Integrin Interactions. CURRENT TOPICS IN MEMBRANES 2015; 76:197-229. [PMID: 26610915 DOI: 10.1016/bs.ctm.2015.07.002] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Laminins are composed of three polypeptide chains, designated as α, β, and γ. The C-terminal region of laminin heterotrimers, containing coiled-coil regions, short tails, and laminin globular (LG) domains, is necessary and sufficient for binding to integrins, which are the major laminin receptor class. Laminin recognition by integrins critically requires the α chain LG domains and a glutamic acid residue of the γ chain at the third position from the C-terminus. Furthermore, the C-terminal region of the β chain contains a short amino acid sequence that modulates laminin affinity for integrins. Thus, all three of the laminin chains act cooperatively to facilitate integrin binding. Mammals possess 5 α (α1-5), 3 β (β1-3), and 3 γ (γ1-3) chains, combinations of which give rise to 16 distinct laminin isoforms. Each isoform is expressed in a tissue-specific and developmental stage-specific manner, exerting its functions through binding of integrins. In this review, we detail the current knowledge surrounding the molecular basis and physiological relevance of specific interactions between laminins and integrins, and describe the mechanisms underlying laminin action through integrins.
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Affiliation(s)
- Masashi Yamada
- Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan
| | - Kiyotoshi Sekiguchi
- Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan
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Coceres VM, Alonso AM, Nievas YR, Midlej V, Frontera L, Benchimol M, Johnson PJ, de Miguel N. The C-terminal tail of tetraspanin proteins regulates their intracellular distribution in the parasite Trichomonas vaginalis. Cell Microbiol 2015; 17:1217-29. [PMID: 25703821 DOI: 10.1111/cmi.12431] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 02/18/2015] [Accepted: 02/18/2015] [Indexed: 01/05/2023]
Abstract
The parasite Trichomonas vaginalis is the causative agent of trichomoniasis, a prevalent sexually transmitted infection. Here, we report the cellular analysis of T.vaginalis tetraspanin family (TvTSPs). This family of membrane proteins has been implicated in cell adhesion, migration and proliferation in vertebrates. We found that the expression of several members of the family is up-regulated upon contact with vaginal ectocervical cells. We demonstrate that most TvTSPs are localized on the surface and intracellular vesicles and that the C-terminal intracellular tails of surface TvTSPs are necessary for proper localization. Analyses of full-length TvTSP8 and a mutant that lacks the C-terminal tail indicates that surface-localized TvTSP8 is involved in parasite aggregation, suggesting a role for this protein in parasite : parasite interaction.
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Affiliation(s)
- V M Coceres
- Laboratorio de Parásitos Anaerobios, Instituto de Investigaciones Biotecnológicas-Instituto Tecnologico Chascomús (IIB-INTECH), CONICET-UNSAM, Chascomus, B7130IWA, Argentina
| | - A M Alonso
- Laboratorio de Parásitos Anaerobios, Instituto de Investigaciones Biotecnológicas-Instituto Tecnologico Chascomús (IIB-INTECH), CONICET-UNSAM, Chascomus, B7130IWA, Argentina
| | - Y R Nievas
- Laboratorio de Parásitos Anaerobios, Instituto de Investigaciones Biotecnológicas-Instituto Tecnologico Chascomús (IIB-INTECH), CONICET-UNSAM, Chascomus, B7130IWA, Argentina
| | - V Midlej
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil
| | - L Frontera
- Laboratorio de Parásitos Anaerobios, Instituto de Investigaciones Biotecnológicas-Instituto Tecnologico Chascomús (IIB-INTECH), CONICET-UNSAM, Chascomus, B7130IWA, Argentina
| | - M Benchimol
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil.,Unigranrio, Universidade do Grande Rio, Rio de Janeiro, Brazil
| | - P J Johnson
- Department of Microbiology, Immunology, Molecular Genetics, University of California, Los Angeles, CA, 90095-1489, USA
| | - N de Miguel
- Laboratorio de Parásitos Anaerobios, Instituto de Investigaciones Biotecnológicas-Instituto Tecnologico Chascomús (IIB-INTECH), CONICET-UNSAM, Chascomus, B7130IWA, Argentina
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Abstract
Tetraspanins are a family of proteins with four transmembrane domains that play a role in many aspects of cell biology and physiology; they are also used by several pathogens for infection and regulate cancer progression. Many tetraspanins associate specifically and directly with a limited number of proteins, and also with other tetraspanins, thereby generating a hierarchical network of interactions. Through these interactions, tetraspanins are believed to have a role in cell and membrane compartmentalization. In this Cell Science at a Glance article and the accompanying poster, we describe the basic principles underlying tetraspanin-based assemblies and highlight examples of how tetraspanins regulate the trafficking and function of their partner proteins that are required for the normal development and function of several organs, including, in humans, the eye, the kidney and the immune system.
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Affiliation(s)
- Stéphanie Charrin
- Inserm, U1004, F-94807, Villejuif, France Université Paris-Sud, Institut André Lwoff, F-94807 Villejuif, France
| | - Stéphanie Jouannet
- Inserm, U1004, F-94807, Villejuif, France Université Paris-Sud, Institut André Lwoff, F-94807 Villejuif, France
| | - Claude Boucheix
- Inserm, U1004, F-94807, Villejuif, France Université Paris-Sud, Institut André Lwoff, F-94807 Villejuif, France
| | - Eric Rubinstein
- Inserm, U1004, F-94807, Villejuif, France Université Paris-Sud, Institut André Lwoff, F-94807 Villejuif, France
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Chandran RR, Iordanou E, Ajja C, Wille M, Jiang L. Gene expression profiling of Drosophila tracheal fusion cells. Gene Expr Patterns 2014; 15:112-23. [PMID: 24928808 DOI: 10.1016/j.gep.2014.05.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 05/27/2014] [Accepted: 05/31/2014] [Indexed: 10/25/2022]
Abstract
The Drosophila trachea is a premier genetic system to investigate the fundamental mechanisms of tubular organ formation. Tracheal fusion cells lead the branch fusion process to form an interconnected tubular network. Therefore, fusion cells in the Drosophila trachea will be an excellent model to study branch fusion in mammalian tubular organs, such as kidneys and blood vessels. The fusion process is a dynamic cellular process involving cell migration, adhesion, vesicle trafficking, cytoskeleton rearrangement, and membrane fusion. To understand how these cellular events are coordinated, we initiated the critical step to assemble a gene expression profile of fusion cells. For this study, we analyzed the expression of 234 potential tracheal-expressed genes in fusion cells during fusion cell development. 143 Tracheal genes were found to encode transcription factors, signal proteins, cytoskeleton and matrix proteins, transporters, and proteins with unknown function. These genes were divided into four subgroups based on their levels of expression in fusion cells compared to neighboring non-fusion cells revealed by in situ hybridization: (1) genes that have relative high abundance in fusion cells, (2) genes that are dynamically expressed in fusion cells, (3) genes that have relative low abundance in fusion cells, and (4) genes that are expressed at similar levels in fusion cells and non-fusion tracheal cells. This study identifies the expression profile of fusion cells and hypothetically suggests genes which are necessary for the fusion process and which play roles in distinct stages of fusion, as indicated by the location and timing of expression. These data will provide the basis for a comprehensive understanding of the molecular and cellular mechanisms of branch fusion.
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Affiliation(s)
- Rachana R Chandran
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States
| | - Ekaterini Iordanou
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States
| | - Crystal Ajja
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States
| | - Michael Wille
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States
| | - Lan Jiang
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States.
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Palmer TD, Martínez CH, Vasquez C, Hebron KE, Jones-Paris C, Arnold SA, Chan SM, Chalasani V, Gomez-Lemus JA, Williams AK, Chin JL, Giannico GA, Ketova T, Lewis JD, Zijlstra A. Integrin-free tetraspanin CD151 can inhibit tumor cell motility upon clustering and is a clinical indicator of prostate cancer progression. Cancer Res 2014; 74:173-87. [PMID: 24220242 PMCID: PMC3947299 DOI: 10.1158/0008-5472.can-13-0275] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins α3β1 and α6β1. However, this interaction cannot explain the ability of CD151 to control migration in the absence of these integrins or on non-laminin substrates. We demonstrate that CD151 can regulate tumor cell migration without direct integrin binding and that integrin-free CD151 (CD151(free)) correlates clinically with tumor progression and metastasis. Clustering CD151(free) through its integrin-binding domain promotes accumulation in areas of cell-cell contact, leading to enhanced adhesion and inhibition of tumor cell motility in vitro and in vivo. CD151(free) clustering is a strong regulator of motility even in the absence of α3 expression but requires PKCα, suggesting that CD151 can control migration independent of its integrin associations. The histologic detection of CD151(free) in prostate cancer correlates with poor patient outcome. When CD151(free) is present, patients are more likely to recur after radical prostatectomy and progression to metastatic disease is accelerated. Multivariable analysis identifies CD151(free) as an independent predictor of survival. Moreover, the detection of CD151(free) can stratify survival among patients with elevated prostate-specific antigen levels. Cumulatively, these studies demonstrate that a subpopulation of CD151 exists on the surface of tumor cells that can regulate migration independent of its integrin partner. The clinical correlation of CD151(free) with prostate cancer progression suggests that it may contribute to the disease and predict cancer progression.
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Affiliation(s)
- Trenis D Palmer
- Authors' Affiliations:Departments of Pathology, Microbiology and Immunology and Cancer Biology, Vanderbilt University, Nashville, Tennessee; Department of Oncology, University of Alberta, Edmonton, Alberta; Translational Prostate Cancer Research Group, London Regional Cancer Program; and Department of Pathology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario Canada
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Abstract
An abundance of evidence shows supporting roles for tetraspanin proteins in human cancer. Many studies show that the expression of tetraspanins correlates with tumour stage, tumour type and patient outcome. In addition, perturbations of tetraspanins in tumour cell lines can considerably affect cell growth, morphology, invasion, tumour engraftment and metastasis. This Review emphasizes new studies that have used de novo mouse cancer models to show that select tetraspanin proteins have key roles in tumour initiation, promotion and metastasis. This Review also emphasizes how tetraspanin proteins can sometimes participate in tumour angiogenesis. These recent data build an increasingly strong case for tetraspanins as therapeutic targets.
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40
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Zhang K, Feng J, Sun Q, Jin L, Li J, Wu X, Han D. A multiple-labelling method for cells using Au nanoparticles with different shapes. CHINESE SCIENCE BULLETIN-CHINESE 2013. [DOI: 10.1007/s11434-013-5794-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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41
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Li Q, Yang XH, Xu F, Sharma C, Wang HX, Knoblich K, Rabinovitz I, Granter SR, Hemler ME. Tetraspanin CD151 plays a key role in skin squamous cell carcinoma. Oncogene 2013; 32:1772-83. [PMID: 22824799 PMCID: PMC3482293 DOI: 10.1038/onc.2012.205] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Revised: 03/30/2012] [Accepted: 04/23/2012] [Indexed: 11/23/2022]
Abstract
Here we provide the first evidence that tetraspanin CD151 can support de novo carcinogenesis. During two-stage mouse skin chemical carcinogenesis, CD151 reduces tumor lag time and increases incidence, multiplicity, size and progression to malignant squamous cell carcinoma (SCC), while supporting both cell survival during tumor initiation and cell proliferation during the promotion phase. In human skin SCC, CD151 expression is selectively elevated compared with other skin cancer types. CD151 support of keratinocyte survival and proliferation may depend on activation of transcription factor STAT3 (signal transducers and activators of transcription), a regulator of cell proliferation and apoptosis. CD151 also supports protein kinase C (PKC)α-α6β4 integrin association and PKC-dependent β4 S1424 phosphorylation, while regulating α6β4 distribution. CD151-PKCα effects on integrin β4 phosphorylation and subcellular localization are consistent with epithelial disruption to a less polarized, more invasive state. CD151 ablation, while minimally affecting normal cell and normal mouse functions, markedly sensitized mouse skin and epidermoid cells to chemicals/drugs including 7,12-dimethylbenz[α]anthracene (mutagen) and camptothecin (topoisomerase inhibitor), as well as to agents targeting epidermal growth factor receptor, PKC, Jak2/Tyk2 and STAT3. Hence, CD151 'co-targeting' may be therapeutically beneficial. These findings not only support CD151 as a potential tumor target, but also should apply to other cancers utilizing CD151/laminin-binding integrin complexes.
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Affiliation(s)
- Qinglin Li
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston MA
| | - Xiuwei H. Yang
- Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, KY
| | - Fenghui Xu
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston MA
| | - Chandan Sharma
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston MA
| | - Hong-Xing Wang
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston MA
| | - Konstantin Knoblich
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston MA
| | - Isaac Rabinovitz
- Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston MA
| | - Scott R. Granter
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston MA
| | - Martin E. Hemler
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston MA
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42
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Gartlan KH, Wee JL, Demaria MC, Nastovska R, Chang TM, Jones EL, Apostolopoulos V, Pietersz GA, Hickey MJ, van Spriel AB, Wright MD. Tetraspanin CD37 contributes to the initiation of cellular immunity by promoting dendritic cell migration. Eur J Immunol 2013; 43:1208-19. [PMID: 23420539 DOI: 10.1002/eji.201242730] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 01/03/2013] [Accepted: 02/13/2013] [Indexed: 12/16/2022]
Abstract
Previous studies on the role of the tetraspanin CD37 in cellular immunity appear contradictory. In vitro approaches indicate a negative regulatory role, whereas in vivo studies suggest that CD37 is necessary for optimal cellular responses. To resolve this discrepancy, we studied the adaptive cellular immune responses of CD37(-/-) mice to intradermal challenge with either tumors or model antigens and found that CD37 is essential for optimal cell-mediated immunity. We provide evidence that an increased susceptibility to tumors observed in CD37(-/-) mice coincides with a striking failure to induce antigen-specific IFN-γ-secreting T cells. We also show that CD37 ablation impairs several aspects of DC function including: in vivo migration from skin to draining lymph nodes; chemo-tactic migration; integrin-mediated adhesion under flow; the ability to spread and form actin protrusions and in vivo priming of adoptively transferred naïve T cells. In addition, multiphoton microscopy-based assessment of dermal DC migration demonstrated a reduced rate of migration and increased randomness of DC migration in CD37(-/-) mice. Together, these studies are consistent with a model in which the cellular defect that underlies poor cellular immune induction in CD37(-/-) mice is impaired DC migration.
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Affiliation(s)
- Kate H Gartlan
- Department of Immunology, Monash University, Prahran, Victoria, Australia
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43
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Harris HJ, Clerte C, Farquhar MJ, Goodall M, Hu K, Rassam P, Dosset P, Wilson GK, Balfe P, IJzendoorn SC, Milhiet PE, McKeating JA. Hepatoma polarization limits CD81 and hepatitis C virus dynamics. Cell Microbiol 2013; 15:430-45. [PMID: 23126643 PMCID: PMC3599488 DOI: 10.1111/cmi.12047] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 09/08/2012] [Accepted: 09/27/2012] [Indexed: 12/12/2022]
Abstract
Many viruses target the polarized epithelial apex during host invasion. In contrast, hepatitis C virus (HCV) engages receptors at the basal surface of hepatocytes in the polarized liver parenchyma. Hepatocyte polarization limits HCV entry by undefined mechanism(s). Given the recent reports highlighting a role for receptor mobility in pathogen entry, we studied the effect(s) of hepatocyte polarization on viral receptor and HCV pseudoparticle (HCVpp) dynamics using real-time fluorescence recovery after photobleaching and single particle tracking. Hepatoma polarization reduced CD81 and HCVpp dynamics at the basal membrane. Since cell polarization is accompanied by changes in the actin cytoskeleton and CD81 links to actin via its C-terminus, we studied the dynamics of a mutant CD81 lacking a C-terminal tail (CD81(ΔC)) and its effect(s) on HCVpp mobility and infection. CD81(ΔC) showed an increased frequency of confined trajectories and a reduction of Brownian diffusing molecules compared to wild-type protein in non-polarized cells. However, these changes were notobserved in polarized cells. HCVpp showed a significant reduction in Brownian diffusion and infection of CD81(ΔC) expressing non-polarized cells. In summary, these data highlight the dynamic nature of CD81 and demonstrate a role for CD81 lateral diffusion to regulate HCV infection in a polarization-dependent manner.
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Affiliation(s)
- H J Harris
- School of Immunity and Infection, University of BirminghamBirmingham, UK
- NIHR Centre for Liver Disease, University of BirminghamBirmingham, UK
| | - C Clerte
- Unité 1054, InsermMontpellier, France
- Centre de Biochimie Structurale, Université de Montpellier, CNRS, UMR 5048Montpellier, France
| | - M J Farquhar
- School of Immunity and Infection, University of BirminghamBirmingham, UK
- NIHR Centre for Liver Disease, University of BirminghamBirmingham, UK
| | - M Goodall
- School of Immunity and Infection, University of BirminghamBirmingham, UK
- NIHR Centre for Liver Disease, University of BirminghamBirmingham, UK
| | - K Hu
- School of Immunity and Infection, University of BirminghamBirmingham, UK
- NIHR Centre for Liver Disease, University of BirminghamBirmingham, UK
| | - P Rassam
- Unité 1054, InsermMontpellier, France
- Centre de Biochimie Structurale, Université de Montpellier, CNRS, UMR 5048Montpellier, France
| | - P Dosset
- Unité 1054, InsermMontpellier, France
- Centre de Biochimie Structurale, Université de Montpellier, CNRS, UMR 5048Montpellier, France
| | - G K Wilson
- School of Immunity and Infection, University of BirminghamBirmingham, UK
- NIHR Centre for Liver Disease, University of BirminghamBirmingham, UK
| | - P Balfe
- School of Immunity and Infection, University of BirminghamBirmingham, UK
- NIHR Centre for Liver Disease, University of BirminghamBirmingham, UK
| | - S C IJzendoorn
- Department of Cell Biology, University Medical Center Groningen, University of GroningenGroningen, The Netherlands
| | - P E Milhiet
- Unité 1054, InsermMontpellier, France
- Centre de Biochimie Structurale, Université de Montpellier, CNRS, UMR 5048Montpellier, France
| | - J A McKeating
- School of Immunity and Infection, University of BirminghamBirmingham, UK
- NIHR Centre for Liver Disease, University of BirminghamBirmingham, UK
- NIHR Liver Biomedical Research Unit, University of BirminghamBirmingham, UK
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Abstract
Human papillomavirus type 16 (HPV16) is the primary etiologic agent for cervical cancer. The infectious entry of HPV16 into cells occurs via a so-far poorly characterized clathrin- and caveolin-independent endocytic pathway, which involves tetraspanin proteins and actin. In this study, we investigated the specific role of the tetraspanin CD151 in the early steps of HPV16 infection. We show that surface-bound HPV16 moves together with CD151 within the plane of the membrane before they cointernalize into endosomes. Depletion of endogenous CD151 did not affect binding of viral particles to cells but resulted in reduction of HPV16 endocytosis. HPV16 uptake is dependent on the C-terminal cytoplasmic region of CD151 but does not require its tyrosine-based sorting motif. Reexpression of the wild-type CD151 but not mutants affecting integrin functions restored virus internalization in CD151-depleted cells. Accordingly, short interfering RNA (siRNA) gene knockdown experiments confirmed that CD151-associated integrins (i.e., α3β1 and α6β1/4) are involved in HPV16 infection. Furthermore, palmitoylation-deficient CD151 did not support HPV16 cell entry. These data show that complex formation of CD151 with laminin-binding integrins and integration of the complex into tetraspanin-enriched microdomains are critical for HPV16 endocytosis.
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45
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Iwasaki T, Takeda Y, Maruyama K, Yokosaki Y, Tsujino K, Tetsumoto S, Kuhara H, Nakanishi K, Otani Y, Jin Y, Kohmo S, Hirata H, Takahashi R, Suzuki M, Inoue K, Nagatomo I, Goya S, Kijima T, Kumagai T, Tachibana I, Kawase I, Kumanogoh A. Deletion of tetraspanin CD9 diminishes lymphangiogenesis in vivo and in vitro. J Biol Chem 2012; 288:2118-31. [PMID: 23223239 DOI: 10.1074/jbc.m112.424291] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Tetraspanins have emerged as key players in malignancy and inflammatory diseases, yet little is known about their roles in angiogenesis, and nothing is known about their involvement in lymphangiogenesis. We found here that tetraspanins are abundantly expressed in human lymphatic endothelial cells (LEC). After intrathoracic tumor implantation, metastasis to lymph nodes was diminished and accompanied by decreased angiogenesis and lymphangiogenesis in tetraspanin CD9-KO mice. Moreover, lymphangiomas induced in CD9-KO mice were less pronounced with decreased lymphangiogenesis compared with those in wild-type mice. Although mouse LEC isolated from CD9-KO mice showed normal adhesion, lymphangiogenesis was markedly impaired in several assays (migration, proliferation, and cable formation) in vitro and in the lymphatic ring assay ex vivo. Consistent with these findings in mouse LEC, knocking down CD9 in human LEC also produced decreased migration, proliferation, and cable formation. Immunoprecipitation analysis demonstrated that deletion of CD9 in LEC diminished formation of functional complexes between VEGF receptor-3 and integrins (α5 and α9). Therefore, knocking down CD9 in LEC attenuated VEGF receptor-3 signaling, as well as downstream signaling such as Erk and p38 upon VEGF-C stimulation. Finally, double deletion of CD9/CD81 in mice caused abnormal development of lymphatic vasculature in the trachea and diaphragm, suggesting that CD9 and a closely related tetraspanin CD81 coordinately play an essential role in physiological lymphangiogenesis. In conclusion, tetraspanin CD9 modulates molecular organization of integrins in LEC, thereby supporting several functions required for lymphangiogenesis.
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Affiliation(s)
- Takeo Iwasaki
- Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
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Copeland BT, Bowman MJ, Ashman LK. Genetic ablation of the tetraspanin CD151 reduces spontaneous metastatic spread of prostate cancer in the TRAMP model. Mol Cancer Res 2012; 11:95-105. [PMID: 23131993 DOI: 10.1158/1541-7786.mcr-12-0468] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Tetraspanins are integral membrane proteins that associate with motility-related molecules such as integrins. Experimental studies have indicated that they may be important regulators of tumor invasion and metastasis, and high expression of the tetraspanin CD151 has been linked to poor prognosis in a number of cancers. Here, we show for the first time that genetic ablation of CD151 inhibits spontaneous metastasis in a transgenic mouse model of de novo tumorigenesis. To evaluate the effects of CD151 on de novo prostate cancer initiation and metastasis, a Cd151(-/-) (KO) murine model was crossed with the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. Mice were analyzed for initiation of prostate tumor by palpation and primary tumors were analyzed by immunohistochemistry. Liver and lungs were examined for incidence and size of spontaneous metastatic lesions by histopathology. Knocking-out Cd151 had no significant effect on prostate cancer initiation or on expression of markers of proliferation, apoptosis, or angiogenesis in primary tumors. However, it did significantly decrease metastasis in a site-specific fashion, notably to the lungs but not the liver. Thus, CD151 acts principally as promoter of metastasis in this model. Prostate cancer is the second highest cause of cancer-related deaths in men in most Western countries, with the majority of deaths attributed to late-stage metastatic disease. CD151 may prove to be a valuable prognostic marker for treatment stratification and is a possible antimetastatic target.
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Affiliation(s)
- Ben T Copeland
- Room 3-04, Life Sciences Building, Callaghan Campus, University Drive, University of Newcastle, Newcastle, New South Wales, Australia 2308.
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Tsujino K, Takeda Y, Arai T, Shintani Y, Inagaki R, Saiga H, Iwasaki T, Tetsumoto S, Jin Y, Ihara S, Minami T, Suzuki M, Nagatomo I, Inoue K, Kida H, Kijima T, Ito M, Kitaichi M, Inoue Y, Tachibana I, Takeda K, Okumura M, Hemler ME, Kumanogoh A. Tetraspanin CD151 protects against pulmonary fibrosis by maintaining epithelial integrity. Am J Respir Crit Care Med 2012; 186:170-80. [PMID: 22592804 DOI: 10.1164/rccm.201201-0117oc] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
RATIONALE Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology with few treatment options. Although tetraspanins are involved in various diseases, their roles in fibrosis have not been determined. OBJECTIVES To investigate the role of tetraspanin CD151 in pulmonary fibrosis. METHODS CD151 knockout (KO) mice were studied by histological, biochemical, and physiological analyses and compared with wild-type mice and CD9 KO mice. Further mechanistic analyses were performed in vitro, in vivo, and on samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS A microarray study identified an enrichment of genes involved in connective tissue disorders in the lungs of CD151 KO mice, but not in CD9 KO mice. Consistent with this, CD151 KO mice spontaneously exhibited age-related pulmonary fibrosis. Deletion of CD151 did not affect pulmonary fibroblast functions but instead degraded epithelial integrity via attenuated adhesion strength on the basement membrane; CD151-deleted alveolar epithelial cells exhibited increased α-SMA expression with activation of p-Smad2, leading to fibrotic changes in the lungs. This loss of epithelial integrity in CD151 KO lungs was further exacerbated by intratracheal bleomycin exposure, resulting in severe fibrosis with increased mortality. We also observed decreased numbers of CD151-positive alveolar epithelial cells in patients with IPF. CONCLUSIONS CD151 is essential for normal function of alveolar epithelial cells; loss of CD151 causes pulmonary fibrosis as a result of epithelial disintegrity. Given that CD151 may protect against fibrosis, this protein represents a novel target for the treatment of fibrotic diseases.
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Affiliation(s)
- Kazuyuki Tsujino
- Department of Respiratory Medicine, Allergy, and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
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Köberle M, Kaesler S, Kempf W, Wölbing F, Biedermann T. Tetraspanins in mast cells. Front Immunol 2012; 3:106. [PMID: 22783251 PMCID: PMC3346162 DOI: 10.3389/fimmu.2012.00106] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Accepted: 04/17/2012] [Indexed: 01/01/2023] Open
Abstract
Mast cells (MC) are key mediators of the immune system, most prominently known for their role in eliciting harmful allergic reactions. Mast cell mediator release (e.g. by degranulation) is triggered by FcεRI recognition of antigen – IgE complexes. Until today no therapeutic targeting of this and other mast cell activation pathways is established. Among possible new candidates there are tetraspanins that have been described on MC already several years ago. Tetraspanins are transmembrane proteins acting as scaffolds, mediating local clustering of their interaction partners, and thus amplify their activities. More recently, tetraspanins were also found to exert intrinsic receptor functions. Tetraspanins have been found to be crucial components of fundamental biological processes like cell motility and adhesion. In immune cells, they not only boost the effectiveness of antigen presentation by clustering MHC molecules, they are also key players in all kinds of degranulation events and immune receptor clustering. This review focuses on the contribution of tetraspanins clustered with FcεRI or residing in granule membranes to classical MC functions but also undertakes an outlook on the possible contribution of tetraspanins to newly described mast cell functions and discusses possible targets for drug development.
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Affiliation(s)
- Martin Köberle
- Department of Dermatology, Eberhard Karls University Tübingen Tübingen, Germany
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Yang XH, Mirchev R, Deng X, Yacono P, Yang HL, Golan DE, Hemler ME. CD151 restricts the α6 integrin diffusion mode. J Cell Sci 2012; 125:1478-87. [PMID: 22328509 DOI: 10.1242/jcs.093963] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Laminin-binding integrins (α3β1, α6β1, α6β4, α7β1) are almost always expressed together with tetraspanin CD151. In every coexpressing cell analyzed to date, CD151 makes a fundamental contribution to integrin-dependent motility, invasion, morphology, adhesion and/or signaling. However, there has been minimal mechanistic insight into how CD151 affects integrin functions. In MDA-MB-231 mammary cells, tetraspanin CD151 knockdown impairs α6 integrin clustering and functions without decreasing α6 integrin expression or activation. Furthermore, CD151 knockdown minimally affects the magnitude of α6 integrin diffusion, as measured using single particle tracking. Instead, CD151 knockdown has a novel and unexpected dysregulating effect on the mode of α6 integrin diffusion. In control cells α6 integrin shows mostly random-confined diffusion (RCD) and some directed motion (DMO). In sharp contrast, in CD151-knockdown cells α6 integrin shows mostly DMO. In control cells α6 diffusion mode is sensitive to actin disruption, talin knockdown and phorbol ester stimulation. By contrast, CD151 knockdown cell α6 integrin is sensitive to actin disruption but desensitized to talin knockdown or phorbol ester stimulation, indicating dysregulation. Both phorbol ester and EGF stimulate cell spreading and promote α6 RCD in control cells. By contrast, CD151-ablated cells retain EGF effects but lose phorbol-ester-stimulated spreading and α6 RCD. For α6 integrins, physical association with CD151 promotes α6 RCD, in support of α6-mediated cable formation and adhesion. By comparison, for integrins not associated with CD151 (e.g. αv integrins), CD151 affects neither diffusion mode nor αv function. Hence, CD151 support of α6 RCD is specific and functionally relevant, and probably underlies diverse CD151 functions in skin, kidney and cancer cells.
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Affiliation(s)
- Xiuwei H Yang
- Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
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Abstract
INTRODUCTION Integrin receptors for cell adhesion to the extracellular matrix have important roles in all stages of cancer progression and metastasis. Since the integrin family was discovered in the early 1980's, many studies have identified critical adhesion and signaling functions for integrins expressed on tumor cells, endothelial cells and other cell types of the tumor microenvironment, in controlling proliferation, survival, migration and angiogenesis. In recent years, the laminin-binding integrin α3β1 has emerged as a potentially promising anti-cancer target on breast cancer cells. AREAS COVERED Studies from the past decade that implicate integrins as promising anti-cancer targets and the development of integrin antagonists as anti-cancer therapeutics. Recent preclinical studies that have identified the laminin-binding integrin α3β1 as an appealing anti-cancer target and the knowledge gaps that must be closed to fully exploit this integrin as a therapeutic target for breast cancer. EXPERT OPINION Although the tumor-promoting functions of α3β1 implicate this integrin as a promising therapeutic target on breast cancer cells, successful exploitation of this integrin as an anti-cancer target will require a better understanding of the molecular mechanisms whereby it regulates specific tumor cell behaviors and the identification of the most appropriate α3β1 functions to antagonize on breast cancer cells.
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Affiliation(s)
- Sita Subbaram
- Albany Medical College, Center for Cell Biology & Cancer Research, Albany, NY 12208, USA
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