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Zheng S, Zhang Y, Cai R, Cai B, Luo S, He S, Peng T, Wang W, Cui H, Li H, Lu X. The untold story of CD82: Exploring its non-canonical roles in cancer. Pathol Res Pract 2025; 270:155979. [PMID: 40252385 DOI: 10.1016/j.prp.2025.155979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 04/06/2025] [Accepted: 04/13/2025] [Indexed: 04/21/2025]
Abstract
CD82, traditionally recognized as a metastasis suppressor within the tetraspanin family, has emerged as a key player in diverse cancer-related processes beyond its canonical functions. This review highlights recent research on the non-canonical roles of CD82 in cancer progression, with a particular focus on its regulation of immune cell interactions, its impact on tumor microenvironment modulation, and its potential as both a therapeutic target and a biomarker. By examining the novel functions of CD82 in immune modulation and its influence on key signaling pathways, we propose that CD82 offers promising avenues for therapeutic interventions in cancer. This paper provides a comprehensive synthesis of the current understanding of CD82's expanded roles, underscoring its potential in improving cancer diagnosis and therapy.
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Affiliation(s)
- Shutao Zheng
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Yao Zhang
- Beijing Beanstalk International Bilingual School, Beijing 100016, PR China
| | - Ren Cai
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Bangwu Cai
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Shujuan Luo
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Shuo He
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Tianyuan Peng
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Wei Wang
- Department of Digestive Internal Medicine, the Affiliated Tumor Hospital of Xinjiang Medical University, PR China
| | - Hong Cui
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Huifang Li
- Department of Breast Surgery, the First Affiliated Hospital of Xinjiang Medical University, PR China
| | - Xiaomei Lu
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China.
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Kim JS, Kim HK, Lee J, Jang S, Cho E, Mun SJ, Yoon S, Yang CS. Inhibition of CD82 improves colitis by increasing NLRP3 deubiquitination by BRCC3. Cell Mol Immunol 2023; 20:189-200. [PMID: 36600050 PMCID: PMC9887069 DOI: 10.1038/s41423-022-00971-1] [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: 06/15/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
CD82 is a transmembrane protein that is involved in cancer suppression and activates immune cells; however, information on the NLRP3 inflammasome is limited. Herein, we show that although CD82 suppressed the activation of the NLRP3 inflammasome in vivo and in vitro, CD82 deficiency decreased the severity of colitis in mice. Furthermore, two binding partners of CD82, NLRP3 and BRCC3, were identified. CD82 binding to these partners increased the degradation of NLRP3 by blocking BRCC3-dependent K63-specific deubiquitination. Previous studies have shown that CD82-specific bacteria in the colon microbiota called Bacteroides vulgatus (B. vulgatus) regulated the expression of CD82 and promoted the activation of the NLRP3 inflammasome. Accordingly, we observed that B. vulgatus administration increased mouse survival by mediating CD82 expression and activating NLRP3 in mice with colitis. Overall, this study showed that CD82 suppression reduced the pathogenesis of colitis by elevating the activation of the NLRP3 inflammasome through BRCC3-dependent K63 deubiquitination. Based on our findings, we propose that B. vulgatus is a novel therapeutic candidate for colitis.
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Affiliation(s)
- Jae-Sung Kim
- Department of Bionano Technology, Hanyang University, Seoul, 04673, Korea
- Institute of Natural Science & Technology, Hanyang University, Ansan, 15588, Korea
| | - Hyo Keun Kim
- Department of Molecular and Life Science, Hanyang University, Ansan, 15588, Korea
- Center for Bionano Intelligence Education and Research, Ansan, 15588, Korea
| | - Joongho Lee
- Department of Computer Science, College of SW Convergence, Dankook University, Yongin, 16890, Korea
| | - Sein Jang
- Department of Molecular and Life Science, Hanyang University, Ansan, 15588, Korea
- Center for Bionano Intelligence Education and Research, Ansan, 15588, Korea
| | - Euni Cho
- Department of Bionano Technology, Hanyang University, Seoul, 04673, Korea
- Center for Bionano Intelligence Education and Research, Ansan, 15588, Korea
| | - Seok-Jun Mun
- Department of Bionano Technology, Hanyang University, Seoul, 04673, Korea
- Center for Bionano Intelligence Education and Research, Ansan, 15588, Korea
| | - Seokhyun Yoon
- Department of Electronics & Electrical Engineering, College of Engineering, Dankook University, Yongin, 16890, Korea
| | - Chul-Su Yang
- Department of Molecular and Life Science, Hanyang University, Ansan, 15588, Korea.
- Center for Bionano Intelligence Education and Research, Ansan, 15588, Korea.
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Wang S, Chen J, Guo XZ. KAI1/CD82 gene and autotaxin-lysophosphatidic acid axis in gastrointestinal cancers. World J Gastrointest Oncol 2022; 14:1388-1405. [PMID: 36160748 PMCID: PMC9412925 DOI: 10.4251/wjgo.v14.i8.1388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/06/2022] [Accepted: 07/22/2022] [Indexed: 02/05/2023] Open
Abstract
The KAI1/CD82 gene inhibits the metastasis of most tumors and is remarkably correlated with tumor invasion and prognosis. Cell metabolism dysregulation is an important cause of tumor occurrence, development, and metastasis. As one of the important characteristics of tumors, cell metabolism dysregulation is attracting increasing research attention. Phospholipids are an indispensable substance in the metabolism in various tumor cells. Phospholipid metabolites have become important cell signaling molecules. The pathological role of lysophosphatidic acid (LPA) in tumors was identified in the early 1990s. Currently, LPA inhibitors have entered clinical trials but are not yet used in clinical treatment. Autotaxin (ATX) has lysophospholipase D (lysoPLD) activity and can regulate LPA levels in vivo. The LPA receptor family and ATX/lysoPLD are abnormally expressed in various gastrointestinal tumors. According to our recent pre-experimental results, KAI1/CD82 might inhibit the migration and metastasis of cancer cells by regulating the ATX-LPA axis. However, no relevant research has been reported. Clarifying the mechanism of ATX-LPA in the inhibition of cancer metastasis by KAI1/CD82 will provide an important theoretical basis for targeted cancer therapy. In this paper, the molecular compositions of the KAI1/CD82 gene and the ATX-LPA axis, their physiological functions in tumors, and their roles in gastrointestinal cancers and target therapy are reviewed.
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Affiliation(s)
- Shuo Wang
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Jiang Chen
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Xiao-Zhong Guo
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
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Ma X, He X, Wang C, Huang X, Li Y, Ma K. Small extracellular ring domain is necessary for CD82/KAI1'anti-metastasis function. Biochem Biophys Res Commun 2021; 557:110-116. [PMID: 33862453 DOI: 10.1016/j.bbrc.2021.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/01/2021] [Accepted: 04/01/2021] [Indexed: 02/05/2023]
Abstract
The peptide mimicking small extracellular loop of CD82/KAI1 has been reported to inhibit tumor cell migration and metastasis. This provides an evidence that small extracellular loop domain should be important for the function of CD82/KAI1. In this paper, to investigate the structure basis for the function of EC1 mimic peptide, we systematically analyzed the effects of each amino acid residue in EC1 mimic peptide on its bioactivity. We found that the interfering with the folding of secondary structure with proline, a potent breaker of secondary structure, completely abolished the migration and metastasis-inhibitory activity of EC1 mimic peptide. This means that the bioactivity of EC1 mimic peptide was conformation-dependent. Next, we substitute with proline for amino acid residues in the small extracellular ring region of CD82/KAI1 by the site-specific mutations to disrupting secondary structure and detected its effect on the function of CD82/KAI1. The results showed that the disturbing the secondary structure of small extracellular ring completely abolished the migration and metastasis-inhibitory activity of CD82/KAI1. These results further provide direct evidence that the small extracellular ring is an important function region of CD82/KAI1.
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Affiliation(s)
- Xiaoguang Ma
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, 116044, China; Department of Respirotory and Clinical Medecine, First Affiliated Hospital of Dalian Medical University, Dalian, China.
| | - Xin He
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, 116044, China.
| | - Congcong Wang
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, 116044, China.
| | - Xiaohua Huang
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, 116044, China; Department of Clinical Biochemistry, College of Laboratory Medicine, Dalian Medical University, Dalian, China.
| | - Ying Li
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, 116044, China; Department of Clinical Laboratory, Second Affiliated Hospital of Dalian Medical University, Dalian, China.
| | - Keli Ma
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, 116044, China.
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Wang S, Chen J, Li H, Qi X, Liu X, Guo X. Metabolomic Detection Between Pancreatic Cancer and Liver Metastasis Nude Mouse Models Constructed by Using the PANC1-KAI1/CD 82 Cell Line. Technol Cancer Res Treat 2021; 20:15330338211045204. [PMID: 34605330 PMCID: PMC8493323 DOI: 10.1177/15330338211045204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 08/20/2021] [Indexed: 02/05/2023] Open
Abstract
Background: Pancreatic cancer (PC) has a poor prognosis and is prone to liver metastasis. The KAI1/CD82 gene inhibits PC metastasis. This study aimed to explore differential metabolites and enrich the pathways in serum samples between PC and liver metastasis nude mouse models stably expressing KAI1/CD82. Methods: KAI1/CD82-PLV-EF1α-MCS-IRES-Puro vector and PANC1 cell line stably expressing KAI1/CD82 were constructed for the first time. This cell line was used to construct 3 PC nude mouse models and 3 liver metastasis nude mouse models. The different metabolites and Kyoto encyclopedia of genes and genomes (KEGG) and human metabolome database (HMDB) enrichment pathways were analyzed using the serum samples of the 2 groups of nude mouse models on the basis of untargeted ultra-performance liquid chromatography-tandem mass spectrometry platform. Results: KAI1/CD82-PLV-EF1α-MCS-IRES-Puro vector and PANC1 cell line stably expressing KAI1/CD82 were constructed successfully, and all nude mouse models survived and developed cancers. Among the 1233 metabolites detected, 18 metabolites (9 upregulated and 9 downregulated) showed differences. In agreement with the literature data, the most significant differences between both groups were found in the levels of bile acids (taurocholic acid, chenodeoxycholic acid), glycine, prostaglandin E2, vitamin D, guanosine monophosphate, and inosine. Bile recreation, primary bile acid biosynthesis, and purine metabolism KEGG pathways and a series of HMDB pathways (P < .05) contained differential metabolites that may be associated with liver metastasis from PC. However, the importance of these metabolites on PC liver metastases remains to be elucidated. Conclusions: Our findings suggested that the metabolomic approach may be a useful method to detect potential biomarkers in PC.
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Affiliation(s)
- Shuo Wang
- General Hospital of Northern Theater Command of China Medical University, Shenyang, Liaoning Province, P.R. China
| | - Jiang Chen
- General Hospital of Northern Theater Command of China Medical University, Shenyang, Liaoning Province, P.R. China
| | - Hongyu Li
- General Hospital of Northern Theater Command of China Medical University, Shenyang, Liaoning Province, P.R. China
| | - Xingshun Qi
- General Hospital of Northern Theater Command of China Medical University, Shenyang, Liaoning Province, P.R. China
| | - Xu Liu
- General Hospital of Northern Theater Command of China Medical University, Shenyang, Liaoning Province, P.R. China
| | - Xiaozhong Guo
- General Hospital of Northern Theater Command of China Medical University, Shenyang, Liaoning Province, P.R. China
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Dodla P, Bhoopalan V, Khoo SK, Miranti C, Sridhar S. Gene expression analysis of human prostate cell lines with and without tumor metastasis suppressor CD82. BMC Cancer 2020; 20:1211. [PMID: 33298014 PMCID: PMC7724878 DOI: 10.1186/s12885-020-07675-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 11/22/2020] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Tetraspanin CD82 is a tumor metastasis suppressor that is known to down regulate in various metastatic cancers. However, the exact mechanism by which CD82 prevents cancer metastasis is unclear. This study aims to identify genes that are regulated by CD82 in human prostate cell lines. METHODS We used whole human genome microarray to obtain gene expression profiles in a normal prostate epithelial cell line that expressed CD82 (PrEC-31) and a metastatic prostate cell line that does not express CD82 (PC3). Then, siRNA silencing was used to knock down CD82 expression in PrEC-31 while CD82 was re-expressed in PC3 to acquire differentially-expressed genes in the respective cell line. RESULTS Differentially-expressed genes with a P < 0.05 were identified in 3 data sets: PrEC-31 (+CD82) vs PrEC-31(-CD82), PC3-57 (+CD82) vs. PC3-5 V (-CD82), and PC3-29 (+CD82) vs. PC3-5 V (-CD82). Top 25 gene lists did not show overlap within the data sets, except (CALB1) the calcium binding protein calbindin 1 which was significantly up-regulated (2.8 log fold change) in PrEC-31 and PC3-29 cells that expressed CD82. Other most significantly up-regulated genes included serine peptidase inhibitor kazal type 1 (SPINK1) and polypeptide N-acetyl galactosaminyl transferase 14 (GALNT14) and most down-regulated genes included C-X-C motif chemokine ligand 14 (CXCL14), urotensin 2 (UTS2D), and fibroblast growth factor 13 (FGF13). Pathways related with cell proliferation and angiogenesis, migration and invasion, cell death, cell cycle, signal transduction, and metabolism were highly enriched in cells that lack CD82 expression. Expression of two mutually inclusive genes in top 100 gene lists of all data sets, runt-related transcription factor (RUNX3) and trefoil factor 3 (TFF3), could be validated with qRT-PCR. CONCLUSION Identification of genes and pathways regulated by CD82 in this study may provide additional insights into the role that CD82 plays in prostate tumor progression and metastasis, as well as identify potential targets for therapeutic intervention.
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Affiliation(s)
- Pushpaja Dodla
- Department of Cell and Molecular Biology, Grand Valley State University, Allendale, MI, 49401, USA
| | - Vanitha Bhoopalan
- Department of Cell and Molecular Biology, Grand Valley State University, Allendale, MI, 49401, USA
| | - Sok Kean Khoo
- Department of Cell and Molecular Biology, Grand Valley State University, Allendale, MI, 49401, USA
| | - Cindy Miranti
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ, 85724, USA
| | - Suganthi Sridhar
- Department of Integrative Biology, University of South Florida, 140, 7Th Avenue S, University of South Florida, St. Petersburg, FL, 33701, USA.
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Wei Y, Shen X, Li L, Cao G, Cai X, Wang Y, Shen H. TM4SF1 inhibits apoptosis and promotes proliferation, migration and invasion in human gastric cancer cells. Oncol Lett 2018; 16:6081-6088. [PMID: 30344751 DOI: 10.3892/ol.2018.9411] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 06/26/2018] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is associated with poor patient prognosis, and so it crucial to investigate the molecular mechanisms underlying the progression of GC. The aim of the present study was to investigate the role of transmembrane-4 L6 family member 1 (TM4SF1) in the progression of GC. TM4SF1 small interfering RNA (siRNA) and TM4SF1-expressing plasmids were employed to regulate TM4SF1 expression. In vitro experiments were performed to determine the effect of TM4SF1 on the expression of apoptosis-associated molecules and determine the role of TM4SF1 in apoptosis, proliferation, migration and invasion using human GC cell lines MGC803 and MKN45. The data of the present study demonstrated that TM4SF1 may regulate the expression of apoptosis-associated molecules at the mRNA and protein levels. TM4SF1 silencing reduced B-cell lymphoma 2 (Bcl2) expression, whilst caspase-3 and Bcl2-associated X expression increased, and upregulating TM4SF1 reversed these changes in GC cells. Furthermore, TM4SF1 knockdown promoted apoptosis while inhibiting the proliferation, migration and invasion of GC cells. Rescue experiments demonstrated that TM4SF1 upregulation reversed the changes induced by transfection with TM4SF1 siRNA. In summary, TM4SF1 is an anti-apoptosis protein associated with the progression of GC. Additional in vivo experiments and clinical trials are required to confirm the possible use of TM4SF1 in tumor therapy.
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Affiliation(s)
- Yunhai Wei
- Department of Gastrointestinal Surgery, Huzhou Central Hospital, Huzhou, Zhejiang 313000, P.R. China
| | - Xiaoying Shen
- Department of Gastrointestinal Surgery, Huzhou Central Hospital, Huzhou, Zhejiang 313000, P.R. China
| | - Liqin Li
- Department of Gastrointestinal Surgery, Huzhou Central Hospital, Huzhou, Zhejiang 313000, P.R. China
| | - Guoliang Cao
- Department of Gastrointestinal Surgery, Huzhou Central Hospital, Huzhou, Zhejiang 313000, P.R. China
| | - Xuhua Cai
- Department of Digestion, Huzhou Central Hospital, Huzhou, Zhejiang 313000, P.R. China
| | - Yan Wang
- Department of Gastrointestinal Surgery, Huzhou Central Hospital, Huzhou, Zhejiang 313000, P.R. China
| | - Hua Shen
- Department of Gastrointestinal Surgery, Huzhou Central Hospital, Huzhou, Zhejiang 313000, P.R. China
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Huang C, Fu C, Wren JD, Wang X, Zhang F, Zhang YH, Connel SA, Chen T, Zhang XA. Tetraspanin-enriched microdomains regulate digitation junctions. Cell Mol Life Sci 2018; 75:3423-3439. [PMID: 29589089 PMCID: PMC6615572 DOI: 10.1007/s00018-018-2803-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 02/18/2018] [Accepted: 03/21/2018] [Indexed: 12/22/2022]
Abstract
Tetraspanins co-emerged with multi-cellular organisms during evolution and are typically localized at the cell–cell interface, [corrected] and form tetraspanin-enriched microdomains (TEMs) by associating with each other and other membrane molecules. Tetraspanins affect various biological functions, but how tetraspanins engage in multi-faceted functions at the cellular level is largely unknown. When cells interact, the membrane microextrusions at the cell-cell interfaces form dynamic, digit-like structures between cells, which we term digitation junctions (DJs). We found that (1) tetraspanins CD9, CD81, and CD82 and (2) TEM-associated molecules integrin α3β1, CD44, EWI2/PGRL, and PI-4P are present in DJs of epithelial, endothelial, and cancer cells. Tetraspanins and their associated molecules also regulate the formation and development of DJs. Moreover, (1) actin cytoskeleton, RhoA, and actomyosin activities and (2) growth factor receptor-Src-MAP kinase signaling, but not PI-3 kinase, regulate DJs. Finally, we showed that DJs consist of various forms in different cells. Thus, DJs are common, interactive structures between cells, and likely affect cell adhesion, migration, and communication. TEMs probably modulate various cell functions through DJs. Our findings highlight that DJ morphogenesis reflects the transition between cell-matrix adhesion and cell-cell adhesion and involves both cell-cell and cell-matrix adhesion molecules.
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Affiliation(s)
- Chao Huang
- Stephenson Cancer Center and Department of Physiology, University of Oklahoma Health Sciences Center, BRC Building West Room 1474, 975 N.E. 10th Street, Oklahoma City, OK, 73104, USA
| | - Chenying Fu
- Stephenson Cancer Center and Department of Physiology, University of Oklahoma Health Sciences Center, BRC Building West Room 1474, 975 N.E. 10th Street, Oklahoma City, OK, 73104, USA
| | - Jonathan D Wren
- Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Xuejun Wang
- Stephenson Cancer Center and Department of Physiology, University of Oklahoma Health Sciences Center, BRC Building West Room 1474, 975 N.E. 10th Street, Oklahoma City, OK, 73104, USA
| | - Feng Zhang
- Stephenson Cancer Center and Department of Physiology, University of Oklahoma Health Sciences Center, BRC Building West Room 1474, 975 N.E. 10th Street, Oklahoma City, OK, 73104, USA
| | - Yanhui H Zhang
- University of Tennessee Health Science Center, Memphis, TN, USA
| | | | - Taosheng Chen
- St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Xin A Zhang
- Stephenson Cancer Center and Department of Physiology, University of Oklahoma Health Sciences Center, BRC Building West Room 1474, 975 N.E. 10th Street, Oklahoma City, OK, 73104, USA.
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Miller J, Dreyer TF, Bächer AS, Sinner EK, Heinrich C, Benge A, Gross E, Preis S, Rother J, Roberts A, Nelles G, Miteva T, Reuning U. Differential tumor biological role of the tumor suppressor KAI1 and its splice variant in human breast cancer cells. Oncotarget 2018; 9:6369-6390. [PMID: 29464079 PMCID: PMC5814219 DOI: 10.18632/oncotarget.23968] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 12/23/2017] [Indexed: 01/30/2023] Open
Abstract
The tetraspanin and tumor suppressor KAI1 is downregulated or lost in many cancers which correlates with poor prognosis. KAI1 acts via physical/functional crosstalk with other membrane receptors. Also, a splice variant of KAI1 (KAI1-SP) has been identified indicative of poor prognosis. We here characterized differential effects of the two KAI1 variants on tumor biological events involving integrin (αvß3) and/or epidermal growth factor receptor (EGF-R). In MDA-MB-231 and -435 breast cancer cells, differential effects were documented on the expression levels of the tumor biologically relevant integrin αvß3 which colocalized with KAI1-WT but not with KAI1-SP. Cellular motility was assessed by video image processing, including motion detection and vector analysis for the quantification and visualization of cell motion parameters. In MDA-MB-231 cells, KAI1-SP provoked a quicker wound gap closure and higher closure rates than KAI1-WT, also reflected by different velocities and average motion amplitudes of singular cells. KAI1-SP induced highest cell motion adjacent to the wound gap borders, whereas in MDA-MB-435 cells a comparable induction of both KAI1 variants was noticed. Moreover, while KAI1-WT reduced cell growth, KAI1-SP significantly increased it going along with a pronounced EGF-R upregulation. KAI1-SP-induced cell migration and proliferation was accompanied by the activation of the focal adhesion and Src kinase. Our findings suggest that splicing of KAI1 does not only abrogate its tumor suppressive functions, but even more, promotes tumor biological effects in favor of cancer progression and metastasis.
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Affiliation(s)
- Julia Miller
- Department for Obstetrics & Gynecology, Technical University of Munich, D-81675 Munich, Germany
| | - Tobias F Dreyer
- Department for Obstetrics & Gynecology, Technical University of Munich, D-81675 Munich, Germany
| | - Anne Sophie Bächer
- Department for Obstetrics & Gynecology, Technical University of Munich, D-81675 Munich, Germany
| | - Eva-Kathrin Sinner
- BOKU, University of Natural Resources and Life Sciences, 1180 Vienna, Austria
| | - Christine Heinrich
- Department for Obstetrics & Gynecology, Technical University of Munich, D-81675 Munich, Germany
| | - Anke Benge
- Department for Obstetrics & Gynecology, Technical University of Munich, D-81675 Munich, Germany
| | - Eva Gross
- Department for Obstetrics & Gynecology, Technical University of Munich, D-81675 Munich, Germany
| | - Sarah Preis
- Department for Obstetrics & Gynecology, Technical University of Munich, D-81675 Munich, Germany
| | - Jan Rother
- Materials Science Laboratory, Sony Europe Ltd ZN Deutschland, D-70327 Stuttgart, Germany
| | - Anthony Roberts
- Materials Science Laboratory, Sony Europe Ltd ZN Deutschland, D-70327 Stuttgart, Germany
| | - Gabriele Nelles
- Materials Science Laboratory, Sony Europe Ltd ZN Deutschland, D-70327 Stuttgart, Germany
| | - Tzenka Miteva
- Materials Science Laboratory, Sony Europe Ltd ZN Deutschland, D-70327 Stuttgart, Germany
| | - Ute Reuning
- Department for Obstetrics & Gynecology, Technical University of Munich, D-81675 Munich, Germany
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10
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Zheng Z, Tian R, Wang P. Roles of KAI1 and nm23 in lymphangiogenesis and lymph metastasis of laryngeal squamous cell carcinoma. World J Surg Oncol 2017; 15:211. [PMID: 29187211 PMCID: PMC5707808 DOI: 10.1186/s12957-017-1279-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 11/15/2017] [Indexed: 11/10/2022] Open
Abstract
Background Lymphatic metastasis contributes to the poor prognosis of laryngeal squamous cell carcinoma (LSCC). This study aimed to investigate the roles of two metastasis suppressor genes, KAI1 and nm23, in lymphangiogenesis and lymph metastasis of LSCC. Methods A total of 45 LSCC patients were enrolled in this study. The positive expression rates of KAI1 and nm23 protein were detected via immunohistochemistry in 45 LSCC and 22 normal laryngeal mucosa adjacent to LSCC. Micro-lymphatic vessel density (MLVD) was detected via immunohistochemistry with the specific antibody D2-40. Associations between KAI1 and nm23 expression and clinical characteristics of LSCC were then evaluated. Results The positive expression rates of KAI1 and nm23 were significantly lower in LSCC than normal laryngeal mucosa (P < 0.05). Significantly lower positive rates of KAI1 and nm23 were found in LSCC with lymphatic metastasis than those without lymphatic metastasis (P < 0.05), whereas MLVD was negatively correlated with the expression of KAI1 and nm23 (P < 0.05). However, no significant associations were found between KAI1 and nm23 expression and clinical characteristics of LSCC (sex, age, disease position, differentiation, and T-stage). Conclusions Both KAI1 and nm23 can inhibit lymphangiogenesis and lymphatic metastasis in LSCC.
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Affiliation(s)
- Zongzhu Zheng
- Department of Otorhinolaryngology, Taian City Central Hospital, Taian, Shandong, 271000, China
| | - Ruihua Tian
- Department of Medical Oncology, Taian City Central Hospital, No. 29 Longtan Road, Taishan District, Taian, Shandong, 271000, China.
| | - Ping Wang
- Department of Geriatrics, Taian City Central Hospital, Taian, Shandong, 271000, China
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11
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Menezes SV, Sahni S, Kovacevic Z, Richardson DR. Interplay of the iron-regulated metastasis suppressor NDRG1 with epidermal growth factor receptor (EGFR) and oncogenic signaling. J Biol Chem 2017; 292:12772-12782. [PMID: 28615452 DOI: 10.1074/jbc.r117.776393] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The iron-regulated metastasis suppressor N-myc downstream-regulated gene 1 (NDRG1) has been shown to inhibit numerous oncogenic signaling pathways in cancer cells. Recent findings have demonstrated that NDRG1 inhibits the ErbB family of receptors, which function as key inducers of carcinogenesis. NDRG1 attenuates ErbB signaling by inhibiting formation of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) and HER2/HER3 heterodimers and by down-regulating EGFR via a mechanism involving its degradation. Understanding the complex interplay between NDRG1, iron, and ErbB signaling is vital for identifying novel, more effective targets for cancer therapy.
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Affiliation(s)
- Sharleen V Menezes
- Molecular Pharmacology and Pathology Program, Department of Pathology, Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Sumit Sahni
- Molecular Pharmacology and Pathology Program, Department of Pathology, Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Zaklina Kovacevic
- Molecular Pharmacology and Pathology Program, Department of Pathology, Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology, Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
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12
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Han T, Shu T, Dong S, Li P, Li W, Liu D, Qi R, Zhang S, Zhang L. Chemokine-like factor-like MARVEL transmembrane domain-containing 3 expression is associated with a favorable prognosis in esophageal squamous cell carcinoma. Oncol Lett 2017; 13:2982-2988. [PMID: 28521405 PMCID: PMC5431419 DOI: 10.3892/ol.2017.5837] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 09/30/2016] [Indexed: 12/31/2022] Open
Abstract
Decreased expression of human chemokine-like factor-like MARVEL transmembrane domain-containing 3 (CMTM3) has been identified in a number of human tumors and tumor cell lines, including gastric and testicular cancer, and PC3, CAL27 and Tca-83 cell lines. However, the association between CMTM3 expression and the clinicopathological features and prognosis of esophageal squamous cell carcinoma (ESCC) patients remains unclear. The aim of the present study was to investigate the correlation between CMTM3 expression and clinicopathological parameters and prognosis in ESCC. CMTM3 mRNA and protein expression was analyzed in ESCC and paired non-tumor tissues by quantitative real-time polymerase chain reaction, western blotting and immunohistochemical analysis. The Kaplan-Meier method was used to plot survival curves and the Cox proportional hazards regression model was also used for univariate and multivariate survival analysis. The results revealed that CMTM3 mRNA and protein expression levels were lower in 82.5% (30/40) and 75% (30/40) of ESCC tissues, respectively, when compared with matched non-tumor tissues. Statistical analysis demonstrated that CMTM3 expression was significantly correlated with lymph node metastasis (P=0.002) and clinical stage (P<0.001) in ESCC tissues. Furthermore, the survival time of ESCC patients exhibiting low CMTM3 expression was significantly shorter than that of ESCC patients exhibiting high CMTM3 expression (P=0.01). In addition, Kaplan-Meier survival analysis revealed that the overall survival time of patients exhibiting low CMTM3 expression was significantly decreased compared with patients exhibiting high CMTM3 expression (P=0.010). Cox multivariate analysis indicated that CMTM3 protein expression was an independent prognostic predictor for ESCC after resection. This study indicated that CMTM3 expression is significantly decreased in ESCC tissues and CMTM3 protein expression in resected tumors may present an effective prognostic biomarker.
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Affiliation(s)
- Tianci Han
- Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Tianci Shu
- Department of Dermatology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Siyuan Dong
- Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Peiwen Li
- Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Weinan Li
- Department of Pathology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Dali Liu
- Department of Pathology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Ruiqun Qi
- Department of Dermatology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Shuguang Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Lin Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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13
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The molecular effect of metastasis suppressors on Src signaling and tumorigenesis: new therapeutic targets. Oncotarget 2016; 6:35522-41. [PMID: 26431493 PMCID: PMC4742122 DOI: 10.18632/oncotarget.5849] [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: 06/15/2015] [Accepted: 08/15/2015] [Indexed: 02/07/2023] Open
Abstract
A major problem for cancer patients is the metastasis of cancer cells from the primary tumor. This involves: (1) migration through the basement membrane; (2) dissemination via the circulatory system; and (3) invasion into a secondary site. Metastasis suppressors, by definition, inhibit metastasis at any step of the metastatic cascade. Notably, Src is a non-receptor, cytoplasmic, tyrosine kinase, which becomes aberrantly activated in many cancer-types following stimulation of plasma membrane receptors (e.g., receptor tyrosine kinases and integrins). There is evidence of a prominent role of Src in tumor progression-related events such as the epithelial–mesenchymal transition (EMT) and the development of metastasis. However, the precise molecular interactions of Src with metastasis suppressors remain unclear. Herein, we review known metastasis suppressors and summarize recent advances in understanding the mechanisms of how these proteins inhibit metastasis through modulation of Src. Particular emphasis is bestowed on the potent metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1) and its interactions with the Src signaling cascade. Recent studies demonstrated a novel mechanism through which NDRG1 plays a significant role in regulating cancer cell migration by inhibiting Src activity. Moreover, we discuss the rationale for targeting metastasis suppressor genes as a sound therapeutic modality, and we review several examples from the literature where such strategies show promise. Collectively, this review summarizes the essential interactions of metastasis suppressors with Src and their effects on progression of cancer metastasis. Moreover, interesting unresolved issues regarding these proteins as well as their potential as therapeutic targets are also discussed.
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14
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Liu W, Yue F, Zheng M, Merlot A, Bae DH, Huang M, Lane D, Jansson P, Lui GYL, Richardson V, Sahni S, Kalinowski D, Kovacevic Z, Richardson DR. The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1. Oncotarget 2016; 6:8851-74. [PMID: 25860930 PMCID: PMC4496188 DOI: 10.18632/oncotarget.3316] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Accepted: 02/08/2015] [Indexed: 11/25/2022] Open
Abstract
N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that plays a key role in regulating signaling pathways involved in mediating cancer cell invasion and migration, including those derived from prostate, colon, etc. However, the mechanisms and molecular targets through which NDRG1 reduces cancer cell invasion and migration, leading to inhibition of cancer metastasis, are not fully elucidated. In this investigation, using NDRG1 over-expression models in three tumor cell-types (namely, DU145, PC3MM and HT29) and also NDRG1 silencing in DU145 and HT29 cells, we reveal that NDRG1 decreases phosphorylation of a key proto-oncogene, cellular Src (c-Src), at a well-characterized activating site (Tyr416). NDRG1-mediated down-regulation of EGFR expression and activation were responsible for the decreased phosphorylation of c-Src (Tyr416). Indeed, NDRG1 prevented recruitment of c-Src to EGFR and c-Src activation. Moreover, NDRG1 suppressed Rac1 activity by modulating phosphorylation of a c-Src downstream effector, p130Cas, and its association with CrkII, which acts as a "molecular switch" to activate Rac1. NDRG1 also affected another signaling molecule involved in modulating Rac1 signaling, c-Abl, which then inhibited CrkII phosphorylation. Silencing NDRG1 increased cell migration relative to the control and inhibition of c-Src signaling using siRNA, or a pharmacological inhibitor (SU6656), prevented this increase. Hence, the role of NDRG1 in decreasing cell migration is, in part, due to its inhibition of c-Src activation. In addition, novel pharmacological agents, which induce NDRG1 expression and are currently under development as anti-metastatic agents, markedly increase NDRG1 and decrease c-Src activation. This study leads to important insights into the mechanism involved in inhibiting metastasis by NDRG1 and how to target these pathways with novel therapeutics.
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Affiliation(s)
- Wensheng Liu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R.China.,Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Fei Yue
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R.China
| | - Minhua Zheng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R.China
| | - Angelica Merlot
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Dong-Hun Bae
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Michael Huang
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Darius Lane
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Patric Jansson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Goldie Yuan Lam Lui
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Vera Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Sumit Sahni
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Danuta Kalinowski
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Zaklina Kovacevic
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
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15
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Shandiz SAS, Farasati S, Saeedi B, Baghbani-Arani F, Asl EA, Keshavarz-Pakseresht B, Rahimi A, Assadi A, Noorbazargan H, Hesari MR, Mirzaie A. Up regulation of KAI1 gene expression and apoptosis effect of imatinib mesylate in gastric adenocarcinoma (AGS) cell line. ASIAN PACIFIC JOURNAL OF TROPICAL DISEASE 2016. [DOI: 10.1016/s2222-1808(15)60996-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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16
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Shandiz SAS, Khosravani M, Mohammadi S, Noorbazargan H, Mirzaie A, Inanlou DN, Jalali MD, Jouzaghkar H, Baghbani-Arani F, Keshavarz-Pakseresht B. Evaluation of imatinib mesylate (Gleevec) on KAI1/CD82 gene expression in breast cancer MCF-7 cells using quantitative real-time PCR. Asian Pac J Trop Biomed 2016. [DOI: 10.1016/j.apjtb.2015.10.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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17
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Araki K, Ebata T, Guo AK, Tobiume K, Wolf SJ, Kawauchi K. p53 regulates cytoskeleton remodeling to suppress tumor progression. Cell Mol Life Sci 2015; 72:4077-94. [PMID: 26206378 PMCID: PMC11114009 DOI: 10.1007/s00018-015-1989-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Revised: 07/06/2015] [Accepted: 07/09/2015] [Indexed: 02/07/2023]
Abstract
Cancer cells possess unique characteristics such as invasiveness, the ability to undergo epithelial-mesenchymal transition, and an inherent stemness. Cell morphology is altered during these processes and this is highly dependent on actin cytoskeleton remodeling. Regulation of the actin cytoskeleton is, therefore, important for determination of cell fate. Mutations within the TP53 (tumor suppressor p53) gene leading to loss or gain of function (GOF) of the protein are often observed in aggressive cancer cells. Here, we highlight the roles of p53 and its GOF mutants in cancer cell invasion from the perspective of the actin cytoskeleton; in particular its reorganization and regulation by cell adhesion molecules such as integrins and cadherins. We emphasize the multiple functions of p53 in the regulation of actin cytoskeleton remodeling in response to the extracellular microenvironment, and oncogene activation. Such an approach provides a new perspective in the consideration of novel targets for anti-cancer therapy.
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Affiliation(s)
- Keigo Araki
- Frontiers of Innovative Research in Science and Technology, Konan University, 7-1-20 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan
- Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan
| | - Takahiro Ebata
- Frontiers of Innovative Research in Science and Technology, Konan University, 7-1-20 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan
| | - Alvin Kunyao Guo
- Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Kei Tobiume
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8553, Japan
| | - Steven John Wolf
- Mechanobiology Institute, National University of Singapore, T-Lab, 5A Engineering Drive 1, Singapore, 117411, Singapore
| | - Keiko Kawauchi
- Frontiers of Innovative Research in Science and Technology, Konan University, 7-1-20 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
- Mechanobiology Institute, National University of Singapore, T-Lab, 5A Engineering Drive 1, Singapore, 117411, Singapore.
- Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki, Kanagawa, 211-8533, Japan.
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18
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Guo J, Fan KX, Xie LI, Xiao JJ, Chen K, Hui LN, Xu ZF. Effect and prognostic significance of the KAI1 gene in human gastric carcinoma. Oncol Lett 2015; 10:2035-2042. [PMID: 26622792 PMCID: PMC4579872 DOI: 10.3892/ol.2015.3604] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Accepted: 06/03/2015] [Indexed: 11/14/2022] Open
Abstract
The present study aimed to explore the effect and mechanism of the Kangai 1 (KAI1) gene in regulating the migration and invasion of gastric carcinoma cells, and the prognostic significance of this gene in gastric cancer patients. Immunohistochemistry and in situ hybridization were used to investigate the role of KAI1 in the progression and prognosis of gastric cancer. The pEGFP-N1-KAI1 plasmid was transfected into human gastric carcinoma SGC7901 cells using liposomes. The effect of transfection with the KAI1 gene was measured using a reverse transcription-semi-quantitative polymerase chain reaction (RT-sqPCR) assay. The Transwell chamber assay was used to study the metastatic and invasive ability of SGC7901 cells. Gastric cancer metastasis-associated genes, including hypoxia-inducible factor (HIF)-1α, matrix metalloproteinase (MMP)-2, MMP-9, basic fibroblast growth factor (bFGF), and urease plasminogen activator (uPA) were measured by RT-sqPCR prior to and following transfection with the KAI1 gene. The expression of KAI1 protein and mRNA was associated with the differentiation degree of gastric cancer, presence of lymph node metastasis, tumor-node-metastasis stage, depth of invasion and the survival time of patients. The migratory and invasive abilities of SGC7901 cells were significantly decreased subsequent to transfection with the KAI1 gene, and the expression of bFGF and uPA was downregulated. It was concluded that the tumor suppressor gene KAI1 inhibits the migration and invasion of gastric carcinoma cells, possibly by suppressing the expression of uPA. Patients that expressed KAI1 may demonstrate an improved prognosis.
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Affiliation(s)
- Jing Guo
- Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong 250031, P.R. China
| | - Kai-Xi Fan
- Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong 250031, P.R. China
| | - L I Xie
- Basic Laboratory, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P.R. China
| | - Jia-Jia Xiao
- Department of Neurology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, P.R. China
| | - Kai Chen
- Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Li-Na Hui
- Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong 250031, P.R. China
| | - Zhong-Fa Xu
- Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong 250031, P.R. China
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19
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Camacho Leal MDP, Sciortino M, Tornillo G, Colombo S, Defilippi P, Cabodi S. p130Cas/BCAR1 scaffold protein in tissue homeostasis and pathogenesis. Gene 2015; 562:1-7. [PMID: 25727852 DOI: 10.1016/j.gene.2015.02.027] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 02/01/2015] [Indexed: 12/11/2022]
Abstract
BCAR1 (also known as p130Cas/BCAR1) is an adaptor protein that belongs to the CAS family of scaffold proteins. In the past years, increasing evidence has demonstrated the ability of p130Cas/BCAR1 to activate signaling originating from mechanical stimuli, cell-extracellular matrix (ECM) adhesion and growth factor stimulation cascades during normal development and disease in various biological models. In this review we will specifically discuss the more recent data on the contribution of p130Cas/BCAR1 in the regulation of tissue homeostasis and its potential implications in pathological conditions.
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Affiliation(s)
| | - Marianna Sciortino
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy
| | - Giusy Tornillo
- European Cancer Stem Cell Research Institute and Cardiff School of Biosciences, Cardiff University, Cardiff, UK
| | - Shana Colombo
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy
| | - Paola Defilippi
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy
| | - Sara Cabodi
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy.
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20
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Upheber S, Karle A, Miller J, Schlaugk S, Gross E, Reuning U. Alternative splicing of KAI1 abrogates its tumor-suppressive effects on integrin αvβ3-mediated ovarian cancer biology. Cell Signal 2014; 27:652-62. [PMID: 25435431 DOI: 10.1016/j.cellsig.2014.11.028] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 11/21/2014] [Indexed: 01/31/2023]
Abstract
Loss or downregulation of the tumor-suppressor KAI1 correlates with poor cancer patient prognosis. KAI1 functions by interacting with other proteins, including integrin cell adhesion and signaling receptors. We previously showed that KAI1 physically and functionally crosstalks with the tumor-biologically relevant integrin αvβ3, thereby suppressing ovarian cancer cell migration and proliferation. Interestingly, in metastases, a KAI1 splice variant had been identified, indicating poor patient prognosis. Thus, we here characterized differential effects of the two KAI1 proteins upon their cellular restoration. Opposite to KAI1, KAI1-splice reduced αvβ3-mediated cell adhesion, thereby inducing cell migration. This was accompanied by elevated αvβ3 levels and drastically elevated focal adhesion kinase activation, however, without any obvious colocalization with αvβ3, as observed for KAI1. Moreover, codistribution of KAI1 with the cell/cell-adhesion molecule E-cadherin was abrogated in KAI1-splice. Whereas KAI1 diminished cell proliferative activity, KAI1-splice prominently enhanced cell proliferation concomitant with elevated transcription and cell-surface expression of the epidermal growth factor receptor. Thus KAI1-splice does not only counteract the tumor-suppressive actions of KAI1, but - beyond that - promotes αvβ3-mediated biological functions in favor of tumor progression and metastasis.
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Affiliation(s)
- Sina Upheber
- Clinical Research Unit, Department for Gynecology & Obstetrics, Technische Universitaet München, Germany
| | - Alexandra Karle
- Clinical Research Unit, Department for Gynecology & Obstetrics, Technische Universitaet München, Germany
| | - Julia Miller
- Clinical Research Unit, Department for Gynecology & Obstetrics, Technische Universitaet München, Germany
| | - Stephanie Schlaugk
- Division of Tumor Genetics, Department for Obstetrics & Gynecology, Technische Universitaet Muenchen, Germany
| | - Eva Gross
- Division of Tumor Genetics, Department for Obstetrics & Gynecology, Technische Universitaet Muenchen, Germany
| | - Ute Reuning
- Clinical Research Unit, Department for Gynecology & Obstetrics, Technische Universitaet München, Germany.
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21
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Wu J, Liang S, Bergholz J, He H, Walsh EM, Zhang Y, Xiao ZX. ΔNp63α activates CD82 metastasis suppressor to inhibit cancer cell invasion. Cell Death Dis 2014; 5:e1280. [PMID: 24901051 PMCID: PMC4611714 DOI: 10.1038/cddis.2014.239] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 04/02/2014] [Accepted: 04/22/2014] [Indexed: 12/21/2022]
Abstract
P63 is a p53 family member involved in multiple facets of biology, including embryonic development, cell proliferation, differentiation, survival, apoptosis, senescence and aging. The p63 gene encodes multiple protein isoforms either with (TAp63) or without (ΔNp63) the N-terminal transactivation domain. Amounting evidence suggests that p63 can function as a tumor suppressor, yet the precise molecular mechanisms, and particularly the specific roles of TAp63 and ΔNp63 in cancer progression, are still largely unclear. Here, we demonstrated that ΔNp63α, the predominant isoform expressed in epithelial cells and squamous cell carcinomas, inhibits cell invasion. Affymetrix gene expression profiling, combined with gain- and loss-of-function analyses and chromatin immunoprecipitation, indicated that cluster of differentiation 82 (CD82), a documented metastasis suppressor, is a direct transcriptional target of ΔNp63α. Expression of ΔNp63α inhibited outgrowth in Matrigel and cancer cell invasion, which was largely reversed by specific ablation of CD82. Conversely, ΔNp63α knockdown led to increased cell invasion, which was reversed by ectopic expression of CD82. Moreover, inhibition of glycogen synthase kinase-3β (GSK3β) by either pharmacological inhibitors or by RNA interference resulted in the downregulation of ΔNp63α and CD82 expression, concomitant with increased cell invasion, independently of β-catenin. Furthermore, decreased expression of p63 and CD82 is correlated with cancer progression. Taken together, this study reveals that ΔNp63α upregulates CD82 to inhibit cell invasion, and suggests that GSK3β can regulate cell invasion by modulating the ΔNp63α–CD82 axis.
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Affiliation(s)
- J Wu
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, 02118, USA
| | - S Liang
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610014, China
| | - J Bergholz
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610014, China
| | - H He
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610014, China
| | - E M Walsh
- Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, USA
| | - Y Zhang
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610014, China
| | - Z-X Xiao
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610014, China
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22
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Dai W, Wang C, Wang F, Wang Y, Shen M, Chen K, Cheng P, Zhang Y, Yang J, Zhu R, Zhang H, Li J, Zheng Y, Lu J, Zhou Y, Xu L, Guo C. Anti-miR-197 inhibits migration in HCC cells by targeting KAI 1/CD82. Biochem Biophys Res Commun 2014; 446:541-548. [PMID: 24613834 DOI: 10.1016/j.bbrc.2014.03.006] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 03/01/2014] [Indexed: 11/28/2022]
Abstract
AIM To investigate the metastatic effects and mechanisms of miR-197 in hepatocellular carcinoma (HCC). METHODS AND RESULTS The levels of miR-197 increased in HCC cells and tissues compared with a normal hepatic cell line (LO2) and adjacent nontumorous liver tissues, respectively. miR-197 expression negatively correlated with CD82 mRNA expression in these cell lines and tissues. Dual luciferase reporter assay and Western blot confirmed a direct interaction between miR-197 and CD82 3'UTR sequences. After miR-197 was silenced in HCC cells, CD82 expression increased. In the presence of human hepatocyte growth factor (HGF), cells silenced for anti-miR-197 exhibited elongated cellular tails and diminished lamellipodia due to reductions in both ROCK activity and the levels of Rac 1 protein. Downregulation of miR-197 along with the upregulation of CD82 in HCC cells resulted in the inhibition of HCC migration and invasion in vitro and in vivo. CONCLUSION Taken together, these data suggest that anti-miR-197 suppresses HCC migration and invasion by targeting CD82. The regulation of the miR-197/CD82 axis could be a novel therapeutic target in future HCC effective therapy.
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Affiliation(s)
- Weiqi Dai
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Chengfen Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Fan Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Yugang Wang
- Department of Gastroenterology, Tong Ren Hospital, Jiaotong University, School of Medicine, Shanghai, China
| | - Miao Shen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Ping Cheng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Yan Zhang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Jing Yang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Rong Zhu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Huawei Zhang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Jingjing Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Yuanyuan Zheng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Ling Xu
- Department of Gastroenterology, Tong Ren Hospital, Jiaotong University, School of Medicine, Shanghai, China.
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China.
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Abstract
UNLABELLED The tumor suppressor p53 is lost or mutated in about half of all human cancers, and in those tumors in which it is wild-type, mechanisms exist to prevent its activation. p53 loss not only prevents incipient tumor cells from undergoing oncogene-induced senescence and apoptosis, but also perturbs cell-cycle checkpoints. This enables p53-deficient tumor cells with DNA damage to continue cycling, creating a permissive environment for the acquisition of additional mutations. Theoretically, this could contribute to the evolution of a cancer genome that is conducive to metastasis. Importantly, p53 loss also results in the disruption of pathways that inhibit metastasis, and transcriptionally defective TP53 mutants are known to gain additional functions that promote metastasis. Here, we review the evidence supporting a role for p53 loss or mutation in tumor metastasis, with an emphasis on breast cancer. SIGNIFICANCE The metastatic potential of tumor cells can be positively infl uenced by loss of p53 or expression of p53 gain-of-function mutants. Understanding the mechanisms by which p53 loss and mutation promote tumor metastasis is crucial to understanding the biology of tumor progression and how to appropriately apply targeted therapies.
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Affiliation(s)
- Emily Powell
- Departments of 1Cancer Biology and 2Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Xie J, Yuan Y, Liu Z, Xiao Y, Zhang X, Qin C, Sheng Z, Xu T, Wang X. CMTM3 is frequently reduced in clear cell renal cell carcinoma and exhibits tumor suppressor activities. Clin Transl Oncol 2013; 16:402-9. [PMID: 23907292 DOI: 10.1007/s12094-013-1092-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Accepted: 07/18/2013] [Indexed: 01/09/2023]
Abstract
PURPOSE CKLF-like MARVEL transmembrane domain containing member 3 (CMTM3) is silenced in many kinds of cancers and inhibits tumor cells growth. We investigated the expression and role of CMTM3 in clear cell renal cell carcinoma (ccRCC). METHODS The expression of CMTM3 was detected in ccRCC tissue microarray, specimens, and cell lines by immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. After transfected with CMTM3 plasmid or vector, the proliferation and migration of ccRCC 786-0 cells were determined by MTT assay and transwell assay, respectively. Furthermore, the anchorage-independent growth of transfected cells was assessed using soft agar colony formation assay. RESULTS CMTM3 was down-regulated in 84 % (63/75) of ccRCC tissues and its expression had no correlation with the gender, age, clinical staging and histologic grade. CMTM3 protein was undetectable by western blot in most detected ccRCC specimens and two RCC cell lines (786-0 and ACHN). qRT-PCR analysis showed that CMTM3 mRNA was dramatically down-regulated in 40 ccRCC cancer tissues as compared with the paired adjacent normal ones. Restoration of CMTM3 significantly suppressed the anchorage-independent growth, proliferation and migration of 786-0 cells. CONCLUSION These results indicate that CMTM3 is significantly down-regulated in ccRCC and exerts remarkable tumor-suppressive functions in 786-0 cells. Reduction of CMTM3 expression may contribute to the pathogenesis of ccRCC and CMTM3 may be a potentially target for therapeutic strategy.
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Affiliation(s)
- J Xie
- Department of Urology, Peking University People's Hospital, Beijing, 100044, People's Republic of China
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25
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Barrett A, Pellet-Many C, Zachary IC, Evans IM, Frankel P. p130Cas: a key signalling node in health and disease. Cell Signal 2012; 25:766-77. [PMID: 23277200 DOI: 10.1016/j.cellsig.2012.12.019] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 12/21/2012] [Indexed: 01/08/2023]
Abstract
p130Cas/breast cancer anti-oestrogen resistance 1 (BCAR1) is a member of the Cas (Crk-associated substrate) family of adaptor proteins, which have emerged as key signalling nodes capable of interactions with multiple proteins, with important regulatory roles in normal and pathological cell function. The Cas family of proteins is characterised by the presence of multiple conserved motifs for protein-protein interactions, and by extensive tyrosine and serine phosphorylations. Recent studies show that p130Cas contributes to migration, cell cycle control and apoptosis. p130Cas is essential during early embryogenesis, with a critical role in cardiovascular development. Furthermore, p130Cas has been reported to be involved in the development and progression of several human cancers. p130Cas is able to perform roles in multiple processes due to its capacity to regulate a diverse array of signalling pathways, transducing signals from growth factor receptor tyrosine kinases, non-receptor tyrosine kinases, and integrins. In this review we summarise the current understanding of the structure, function, and regulation of p130Cas, and discuss the importance of p130Cas in both physiological and pathophysiological settings, with a focus on the cardiovascular system and cancer.
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Affiliation(s)
- Angela Barrett
- Centre for Cardiovascular Biology and Medicine, Division of Medicine, University College London, London WC1E 6JJ, United Kingdom.
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26
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Liu WM, Zhang F, Moshiach S, Zhou B, Huang C, Srinivasan K, Khurana S, Zheng Y, Lahti JM, Zhang XA. Tetraspanin CD82 inhibits protrusion and retraction in cell movement by attenuating the plasma membrane-dependent actin organization. PLoS One 2012; 7:e51797. [PMID: 23251627 PMCID: PMC3522597 DOI: 10.1371/journal.pone.0051797] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2011] [Accepted: 11/12/2012] [Indexed: 11/18/2022] Open
Abstract
To determine how tetraspanin KAI1/CD82, a tumor metastasis suppressor, inhibits cell migration, we assessed which cellular events critical for motility are altered by KAI1/CD82 and how KAI1/CD82 regulates these events. We found that KAI1/CD82-expressing cells typically exhibited elongated cellular tails and diminished lamellipodia. Live imaging demonstrated that the polarized protrusion and retraction of the plasma membrane became deficient upon KAI1/CD82 expression. The deficiency in developing these motility-related cellular events was caused by poor formations of actin cortical network and stress fiber and by aberrant dynamics in actin organization. Rac1 activity was reduced by KAI1/CD82, consistent with the diminution of lamellipodia and actin cortical network; while the growth factor-stimulated RhoA activity was blocked by KAI1/CD82, consistent with the loss of stress fiber and attenuation in cellular retraction. Upon KAI1/CD82 expression, Rac effector cofilin was not enriched at the cell periphery to facilitate lamellipodia formation while Rho kinase exhibited a significantly lower activity leading to less retraction. Phosphatidylinositol 4, 5-biphosphate, which initiates actin polymerization from the plasma membrane, became less detectable at the cell periphery in KAI1/CD82-expressing cells. Moreover, KAI1/CD82-induced phenotypes likely resulted from the suppression of multiple signaling pathways such as integrin and growth factor signaling. In summary, at the cellular level KAI1/CD82 inhibited polarized protrusion and retraction events by disrupting actin reorganization; at the molecular level, KAI1/CD82 deregulated Rac1, RhoA, and their effectors cofilin and Rho kinase by perturbing the plasma membrane lipids.
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Affiliation(s)
- Wei M. Liu
- Vascular Biology and Cancer Centers and Departments of Medicine and Molecular Science, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Feng Zhang
- Vascular Biology and Cancer Centers and Departments of Medicine and Molecular Science, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Simon Moshiach
- Department of Genetics and Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America
| | - Bin Zhou
- Vascular Biology and Cancer Centers and Departments of Medicine and Molecular Science, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Chao Huang
- Vascular Biology and Cancer Centers and Departments of Medicine and Molecular Science, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Kamalakkannan Srinivasan
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Seema Khurana
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Yi Zheng
- Division of Experimental Hematology, Cincinnati Children's Hospital, Cincinnati, Ohio, United States of America
| | - Jill M. Lahti
- Department of Genetics and Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America
| | - Xin A. Zhang
- Vascular Biology and Cancer Centers and Departments of Medicine and Molecular Science, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
- * E-mail:
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27
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Guo Q, Xia B, Zhang F, Richardson MM, Li M, Zhang JS, Chen F, Zhang XA. Tetraspanin CO-029 inhibits colorectal cancer cell movement by deregulating cell-matrix and cell-cell adhesions. PLoS One 2012; 7:e38464. [PMID: 22679508 PMCID: PMC3367972 DOI: 10.1371/journal.pone.0038464] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2011] [Accepted: 05/06/2012] [Indexed: 12/14/2022] Open
Abstract
Alterations in tetraspanin CO-029 expression are associated with the progression and metastasis of cancers in the digestive system. However, how CO-029 promotes cancer metastasis is still poorly understood. To determine the mechanism, we silenced CO-029 expression in HT29 colon cancer cells and found that the CO-029 knockdown significantly reduced cell migratory ability. The diminished cell migration was accompanied by the upregulation of both integrin-dependent cell-matrix adhesion on laminin and calcium-dependent cell-cell adhesion. The cell surface levels of laminin-binding integrin α3β1 and fibronectin-integrin α5β1 were increased while the level of CD44 was decreased upon CO-029 silencing. These changes contribute to the altered cell-matrix adhesion. The deregulated cell-cell adhesion results, at least partially, from increased activity of cadherins and reduced level of MelCAM. In conclusion, CO-029 functions as a regulator of both cell-matrix and cell-cell adhesion. During colon cancer progression, CO-029 promotes cancer cell movement by deregulating cell adhesions.
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Affiliation(s)
- Qiusha Guo
- Vascular Biology and Cancer Centers and Departments of Medicine and Molecular Science, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
- Department of Gastroenterology, Zhongnan Hospital, Wuhan University Medical School, Wuhan, China
- Internal Medicine, Renal Division, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Bing Xia
- Department of Gastroenterology, Zhongnan Hospital, Wuhan University Medical School, Wuhan, China
- * E-mail: (XAZ); (BX)
| | - Feng Zhang
- Vascular Biology and Cancer Centers and Departments of Medicine and Molecular Science, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Mekel M. Richardson
- Vascular Biology and Cancer Centers and Departments of Medicine and Molecular Science, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Minghao Li
- Vascular Biology and Cancer Centers and Departments of Medicine and Molecular Science, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Julian S. Zhang
- Vascular Biology and Cancer Centers and Departments of Medicine and Molecular Science, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Feng Chen
- Internal Medicine, Renal Division, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Xin A. Zhang
- Vascular Biology and Cancer Centers and Departments of Medicine and Molecular Science, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
- * E-mail: (XAZ); (BX)
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28
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Park JJ, Jin YB, Lee YJ, Lee JS, Lee YS, Ko YG, Lee M. KAI1 suppresses HIF-1α and VEGF expression by blocking CDCP1-enhanced Src activation in prostate cancer. BMC Cancer 2012; 12:81. [PMID: 22390300 PMCID: PMC3313899 DOI: 10.1186/1471-2407-12-81] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Accepted: 03/06/2012] [Indexed: 01/24/2023] Open
Abstract
Background KAI1 was initially identified as a metastasis-suppressor gene in prostate cancer. It is a member of the tetraspan transmembrane superfamily (TM4SF) of membrane glycoproteins. As part of a tetraspanin-enriched microdomain (TEM), KAI1 inhibits tumor metastasis by negative regulation of Src. However, the underlying regulatory mechanism has not yet been fully elucidated. CUB-domain-containing protein 1 (CDCP1), which was previously known as tetraspanin-interacting protein in TEM, promoted metastasis via enhancement of Src activity. To better understand how KAI1 is involved in the negative regulation of Src, we here examined the function of KAI1 in CDCP1-mediated Src kinase activation and the consequences of this process, focusing on HIF-1 α and VEGF expression. Methods We used the human prostate cancer cell line PC3 which was devoid of KAI1 expression. Vector-transfected cells (PC3-GFP clone #8) and KAI1-expressing PC3 clones (PC3-KAI1 clone #5 and #6) were picked after stable transfection with KAI1 cDNA and selection in 800 μg/ml G418. Protein levels were assessed by immunoblotting and VEGF reporter gene activity was measured by assaying luciferase activitiy. We followed tumor growth in vivo and immunohistochemistry was performed for detection of HIF-1, CDCP1, and VHL protein level. Results We demonstrated that Hypoxia-inducible factor 1α (HIF-1α) and VEGF expression were significantly inhibited by restoration of KAI1 in PC3 cells. In response to KAI1 expression, CDCP1-enhanced Src activation was down-regulated and the level of von Hippel-Lindau (VHL) protein was significantly increased. In an in vivo xenograft model, KAI1 inhibited the expression of CDCP1 and HIF-1α. Conclusions These novel observations may indicate that KAI1 exerts profound metastasis-suppressor activity in the tumor malignancy process via inhibition of CDCP1-mediated Src activation, followed by VHL-induced HIF-1α degradation and, ultimately, decreased VEGF expression.
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Affiliation(s)
- Jung-Jin Park
- Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Nowon-Ku, Seoul 139-706, Korea
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29
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Niediek V, Born S, Hampe N, Kirchgessner N, Merkel R, Hoffmann B. Cyclic stretch induces reorientation of cells in a Src family kinase- and p130Cas-dependent manner. Eur J Cell Biol 2011; 91:118-28. [PMID: 22178114 DOI: 10.1016/j.ejcb.2011.10.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2011] [Revised: 10/23/2011] [Accepted: 10/26/2011] [Indexed: 12/21/2022] Open
Abstract
Recognition of external mechanical signals by cells is an essential process for life. One important mechanical signal experienced by various cell types, e.g. around blood vessels, within the lung epithelia or around the intestine, is cyclic stretch. As a response, many cell types reorient their actin cytoskeleton and main cell axis almost perpendicular to the direction of stretch. Despite the vital necessity of cellular adaptation to cyclic stretch, the underlying mechanosensory signal cascades are far from being understood. Here we show an important function of Src-family kinase activity in cellular reorientation upon cyclic stretch. Deletion of all three family members, namely c-Src, Yes and Fyn (SYF), results in a strongly impaired cell reorientation of mouse embryonic fibroblasts with an only incomplete reorientation upon expression of c-Src. We further demonstrate that this reorientation phenotype of SYF-depleted cells is not caused by affected protein exchange dynamics within focal adhesions or altered cell force generation. Instead, Src-family kinases regulate the reorientation in a mechanotransduction-dependent manner, since knock-down and knock-out of p130Cas, a putative stretch sensor known to be phosphorylated by Src-family kinases, also reduce cellular reorientation upon cyclic stretch. This impaired reorientation is identical in intensity upon mutating stretch-sensitive tyrosines of p130Cas only. These statistically highly significant data pinpoint early events in a Src family kinase- and p130Cas-dependent mechanosensory/mechanotransduction pathway.
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Affiliation(s)
- Verena Niediek
- Institute of Complex Systems 7, Biomechanics, Forschungszentrum Jülich, 52425 Jülich, Germany
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30
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Tsai YC, Weissman AM. Dissecting the diverse functions of the metastasis suppressor CD82/KAI1. FEBS Lett 2011; 585:3166-73. [PMID: 21875585 PMCID: PMC3409691 DOI: 10.1016/j.febslet.2011.08.031] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Revised: 08/19/2011] [Accepted: 08/19/2011] [Indexed: 01/22/2023]
Abstract
The recent identification of metastasis suppressor genes, the products of which inhibit metastasis but not primary tumor growth, distinguishes oncogenic transformation and tumor suppression from a hallmark of malignancy, the ability of cancer cells to invade sites distant from the primary tumor. The metastasis suppressor CD82/KAI1 is a member of the tetraspanin superfamily of glycoproteins. CD82 suppresses metastasis by multiple mechanisms including inhibition of cell motility and invasion, promotion of cell polarity as well as induction of senescence and apoptosis in response to extracellular stimuli. A common feature of these diverse effects is CD82 regulation of membrane organization as well as protein trafficking and interactions, which affects cellular signaling and intercellular communication.
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Affiliation(s)
- Yien Che Tsai
- Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States.
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31
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Cui RH, Chen JQ, Sun M, Sun ZZ. Celecoxib inhibits cell growth and up-regulates KAI1/CD82 protein expression in human hepatocellular carcinoma cell line HepG2. Shijie Huaren Xiaohua Zazhi 2011; 19:1336-1341. [DOI: 10.11569/wcjd.v19.i13.1336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of celecoxib on cell proliferation, apoptosis and KAI1/CD82 expression in human hepatocellular carcinoma cell line HepG2.
METHODS: After HepG2 cells were treated with different concentrations of celecoxib (12.5, 25.0, 50.0, 100.0, 200.0 μmol/L), cell proliferation was measured by CCK-8 assay, cell apoptosis was detected by flow cytometry, and the expression of KAI1/CD82 protein was detected by Western blot.
RESULTS: Treatment with celecoxib significantly inhibited the proliferation of HepG2 cells (P < 0.05) in a dose- and time-dependent manner, and the reduced rate of growth of HepG2 cells treated with 200.0 μmol/L celecoxib for 72 h was 69.23%. Treatment with celecoxib induced apoptosis of HepG2 cells in a dose-dependent manner. The apoptosis rates of cells treated with 12.5, 50.0, or 200.0 μmol/L celecoxib for 48 h were significantly higher than that of control cells (18.79% ± 2.37%, 46.94% ± 0.78%, 69.48% ± 0.63% vs 16.72% ± 1.54%, all P < 0.05). Treatment with celecoxib significantly up-regulated the expression of KAI1/CD82 protein in a dose-dependent manner (48 h: 0.394 ± 0.007, 0.886 ± 0.057, 1.099 ± 0.079 vs 0.321 ± 0.020, all P < 0.05).
CONCLUSION: Celecoxib inhibits cell proliferation and induces apoptosis possibly by up-regulating KAI1/CD82 protein expression in human hepatocellular carcinoma cell line HepG2.
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32
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Fromont G, Cussenot O. The integrin signalling adaptor p130CAS is also a key player in prostate cancer. Nat Rev Cancer 2011; 11:227. [PMID: 21346785 DOI: 10.1038/nrc2967-c1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Tetraspanins and tumor progression. Clin Exp Metastasis 2010; 28:261-70. [DOI: 10.1007/s10585-010-9365-5] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2010] [Accepted: 11/30/2010] [Indexed: 02/07/2023]
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Sun W, Yang J. Functional mechanisms for human tumor suppressors. J Cancer 2010; 1:136-40. [PMID: 20922055 PMCID: PMC2948218 DOI: 10.7150/jca.1.136] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2010] [Accepted: 09/13/2010] [Indexed: 12/19/2022] Open
Abstract
Tumor suppressors refer to a large group of molecules that are capable of controlling cell division, promoting apoptosis, and suppressing metastasis. The loss of function for a tumor suppressor may lead to cancer due to uncontrolled cell division. Because of their importance, extensive studies have been undertaken to understand the different functional mechanisms of tumor suppressors. Here, we briefly review the four major mechanisms, inhibition of cell division, induction of apoptosis, DNA damage repair, and inhibition of metastasis. It is noteworthy that some tumor suppressors, such as p53, may adopt more than one mechanism for their functions.
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Affiliation(s)
- Wanpeng Sun
- Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada
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35
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Tikhmyanova N, Little JL, Golemis EA. CAS proteins in normal and pathological cell growth control. Cell Mol Life Sci 2010; 67:1025-48. [PMID: 19937461 PMCID: PMC2836406 DOI: 10.1007/s00018-009-0213-1] [Citation(s) in RCA: 150] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2009] [Revised: 11/03/2009] [Accepted: 11/09/2009] [Indexed: 12/20/2022]
Abstract
Proteins of the CAS (Crk-associated substrate) family (BCAR1/p130Cas, NEDD9/HEF1/Cas-L, EFS/SIN and CASS4/HEPL) are integral players in normal and pathological cell biology. CAS proteins act as scaffolds to regulate protein complexes controlling migration and chemotaxis, apoptosis, cell cycle, and differentiation, and have more recently been linked to a role in progenitor cell function. Reflecting these complex functions, over-expression of CAS proteins has now been strongly linked to poor prognosis and increased metastasis in cancer, as well as resistance to first-line chemotherapeutics in multiple tumor types including breast and lung cancers, glioblastoma, and melanoma. Further, CAS proteins have also been linked to additional pathological conditions including inflammatory disorders, Alzheimer's and Parkinson's disease, as well as developmental defects. This review will explore the roles of the CAS proteins in normal and pathological states in the context of the many mechanistic insights into CAS protein function that have emerged in the past decade.
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Affiliation(s)
- Nadezhda Tikhmyanova
- Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111 USA
- Department of Biochemistry, Drexel University Medical School, Philadelphia, PA 19102 USA
| | - Joy L. Little
- Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111 USA
| | - Erica A. Golemis
- Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111 USA
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Abstract
Within the integrin family of cell adhesion receptors, integrins alpha3beta1, alpha6beta1, alpha6beta4 and alpha7beta1 make up a laminin-binding subfamily. The literature is divided on the role of these laminin-binding integrins in metastasis, with different studies indicating either pro- or antimetastatic functions. The opposing roles of the laminin-binding integrins in different settings might derive in part from their unusually robust associations with tetraspanin proteins. Tetraspanins organise integrins into multiprotein complexes within discrete plasma membrane domains termed tetraspanin-enriched microdomains (TEMs). TEM association is crucial to the strikingly rapid cell migration mediated by some of the laminin-binding integrins. However, emerging data suggest that laminin-binding integrins also promote the stability of E-cadherin-based cell-cell junctions, and that tetraspanins are essential for this function as well. Thus, TEM association endows the laminin-binding integrins with both pro-invasive functions (rapid migration) and anti-invasive functions (stable cell junctions), and the composition of TEMs in different cell types might help determine the balance between these opposing activities. Unravelling the tetraspanin control mechanisms that regulate laminin-binding integrins will help to define the settings where inhibiting the function of these integrins would be helpful rather than harmful, and may create opportunities to modulate integrin activity in more sophisticated ways than simple functional blockade.
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Xu C, Zhang YH, Thangavel M, Richardson MM, Liu L, Zhou B, Zheng Y, Ostrom RS, Zhang XA. CD82 endocytosis and cholesterol-dependent reorganization of tetraspanin webs and lipid rafts. FASEB J 2009; 23:3273-88. [PMID: 19497983 DOI: 10.1096/fj.08-123414] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Tetraspanin CD82 suppresses cell migration, tumor invasion, and tumor metastasis. To determine the mechanism by which CD82 inhibits motility, most studies have focused on the cell surface CD82, which forms tetraspanin-enriched microdomains (TEMs) with other transmembrane proteins, such as integrins. In this study, we found that CD82 undergoes endocytosis and traffics to endosomes and lysosomes. To determine the endocytic mechanism of CD82, we demonstrated that dynamin and clathrin are not essential for CD82 internalization. Depletion or sequestration of sterol in the plasma membrane markedly inhibited the endocytosis of CD82. Despite the demand on Cdc42 activity, CD82 endocytosis is distinct from macropinocytosis and the documented dynamin-independent pinocytosis. As a TEM component, CD82 reorganizes TEMs and lipid rafts by redistributing cholesterol into these membrane microdomains. CD82-containing TEMs are characterized by the cholesterol-containing microdomains in the extreme light- and intermediate-density fractions. Moreover, the endocytosis of CD82 appears to alleviate CD82-mediated inhibition of cell migration. Taken together, our studies demonstrate that lipid-dependent endocytosis drives CD82 trafficking to late endosomes and lysosomes, and CD82 reorganizes TEMs and lipid rafts through redistribution of cholesterol.
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Affiliation(s)
- Congfeng Xu
- Vascular Biology Center, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Tumor suppressor KAI1 affects integrin αvβ3-mediated ovarian cancer cell adhesion, motility, and proliferation. Exp Cell Res 2009; 315:1759-71. [DOI: 10.1016/j.yexcr.2009.01.007] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2008] [Revised: 01/09/2009] [Accepted: 01/09/2009] [Indexed: 02/07/2023]
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Abstract
Despite high expression levels at the plasma membrane or in intracellular vesicles, tetraspanins remain among the most mysterious transmembrane molecules 20 years after their discovery. Several genetic studies in mammals and invertebrates have demonstrated key physiological roles for some of these tetraspanins, in particular in the immune response, sperm-egg fusion, photoreceptor function and the normal function of certain epithelia. Other studies have highlighted their ability to modulate cell migration and metastasis formation. Their role in the propagation of infectious agents has drawn recent attention, with evidence for HIV budding in tetraspanin-enriched plasma membrane domains. Infection of hepatocytic cells by two major pathogens, the hepatitis C virus and the malaria parasite, also requires the tetraspanin CD81. The function of tetraspanins is thought to be linked to their ability to associate with one another and a wealth of other integral proteins, thereby building up an interacting network or 'tetraspanin web'. On the basis of the biochemical dissection of the tetraspanin web and recent analysis of the dynamics of some of its constituents, we propose that tetraspanins tightly regulate transient interactions between a variety of molecules and as such favour the efficient assembly of specialized structures upon proper stimulation.
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40
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Bai W, Wang L, Ji W, Gao H. Expression profiling of supraglottic carcinoma: PTEN and thrombospondin 2 are associated with inhibition of lymphatic metastasis. Acta Otolaryngol 2009; 129:569-74. [PMID: 18720079 DOI: 10.1080/00016480802294351] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
CONCLUSION Down-regulation of metastasis inhibitor genes PTEN and thrombospondin 2 may play a role in the lymphatic metastasis of supraglottic carcinoma. OBJECTIVES To investigate differentially expressed genes in supraglottic squamous cell carcinoma with and without lymphatic metastasis using cDNA microarray. MATERIALS AND METHODS cDNA microarray was used to detect the expression profiles of supraglottic carcinoma and the results were validated with real-time PCR. RESULTS Compared with normal laryngeal tissues, the expression of 15.6% (15/96) genes including cathepsin B, cathepsin D, cathepsin L, Ets1, c-Ets2, and PEA3 were up-regulated in both cases of supraglottic carcinoma. Compared with the supraglottic carcinoma with no lymph node metastasis, the expression of metastasis inhibitor genes PTEN and thrombospondin 2 was down-regulated in the supraglottic carcinoma tissue with lymph node metastasis.
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41
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Choi UJ, Jee BK, Lim Y, Lee KH. KAI1/CD82 decreases Rac1 expression and cell proliferation through PI3K/Akt/mTOR pathway in H1299 lung carcinoma cells. Cell Biochem Funct 2009; 27:40-7. [PMID: 19107873 DOI: 10.1002/cbf.1532] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Although the KAI1/CD82 protein has been reported to inhibit cell metastasis in many studies, its mechanism of action has not yet been fully elucidated. In the present study, we investigated the possible effects of KAI1/CD82 on the metastatic phenotype in H1299 lung carcinoma cells. These studies were based on the pivotal role that the acquisition of motile phenotype plays on the initial steps of metastasis. KAI1/CD82-mediated morphological changes were observed using phase contrast microscopy. We report here, that a KAI1/CD82-induced phenotypic change was involved in the decrease of Rac1 expression and GTPase activity. However, we found that KAI1/CD82 did not regulate Rac1 mRNA levels. This suggests the existence of another regulatory mechanism of Rac1 protein maturation or activation. To identify the signaling pathway of Rac1 regulation, we investigated the PI3K/Akt/mTOR pathway, since the PI3K/Akt pathway regulates Rac1 activation and mTOR is known to play a regulatory role in protein translation. H1299/CD82-transfectants showed lower mTOR expression and cell growth than the control group. The data obtained from this study suggested that KAI1/CD82 decreased the metastatic phenotype of H1299 lung carcinoma cells by down-regulating Rac1 expression through the PI3K/Akt/mTOR pathway.
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Affiliation(s)
- Un-Jong Choi
- Department of General Surgery, Wonkwang University School of Medicine, Iksan-City, Jeonbuk, Republic of Korea
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42
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Bari R, Zhang YH, Zhang F, Wang NX, Stipp CS, Zheng JJ, Zhang XA. Transmembrane interactions are needed for KAI1/CD82-mediated suppression of cancer invasion and metastasis. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 174:647-60. [PMID: 19116362 DOI: 10.2353/ajpath.2009.080685] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
In transmembrane (TM) domains, tetraspanin KAI1/CD82 contains an Asn, a Gln, and a Glu polar residue. A mutation of all three polar residues largely disrupts the migration-, invasion-, and metastasis-suppressive activities of KAI1/CD82. Notably, KAI1/CD82 inhibits the formation of microprotrusions and the release of microvesicles, while the mutation disrupts these inhibitions, revealing the connections of microprotrusion and microvesicle to KAI1/CD82 function. The TM polar residues are needed for proper interactions between KAI1/CD82 and tetraspanins CD9 and CD151, which also regulate cell movement, but not for the association between KAI1/CD82 and alpha3beta1 integrin. However, KAI1/CD82 still efficiently inhibits cell migration when either CD9 or CD151 is absent. Hence, KAI1/CD82 interacts with tetraspanin and integrin by different mechanisms and is unlikely to inhibit cell migration through its associated proteins. Moreover, without significantly affecting the glycosylation, homodimerization, and global folding of KAI1/CD82, the TM interactions maintain the conformational stability of KAI1/CD82, evidenced by the facts that the mutant is more sensitive to denaturation and less associable with tetraspanins and supported by the modeling analysis. Thus, the TM interactions mediated by these polar residues determine a conformation either in or near the tightly packed TM region and this conformation and/or its change are needed for the intrinsic activity of KAI1/CD82. In contrast to immense efforts to block the signaling of cancer progression, the perturbation of TM interactions may open a new avenue to prevent cancer invasion and metastasis.
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Affiliation(s)
- Rafijul Bari
- Vascular Biology Center, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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43
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Miranti CK. Controlling cell surface dynamics and signaling: how CD82/KAI1 suppresses metastasis. Cell Signal 2008; 21:196-211. [PMID: 18822372 DOI: 10.1016/j.cellsig.2008.08.023] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2008] [Accepted: 08/24/2008] [Indexed: 12/29/2022]
Abstract
The recent identification of metastasis suppressor genes, uniquely responsible for negatively controlling cancer metastasis, are providing inroads into the molecular machinery involved in metastasis. While the normal function of a few of these genes is known; the molecular events associated with their loss that promotes tumor metastasis is largely not understood. KAI1/CD82, whose loss is associated with a wide variety of metastatic cancers, belongs to the tetraspanin family. Despite intense scrutiny, many aspects of how CD82 specifically functions as a metastasis suppressor and its role in normal biology remain to be determined. This review will focus on the molecular events associated with CD82 loss, the potential impact on signaling pathways that regulate cellular processes associated with metastasis, and its relationship with other metastasis suppressor genes.
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Affiliation(s)
- C K Miranti
- Laboratory of Integrin Signaling, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, United States.
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44
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Mu Z, Wang H, Zhang J, Li Q, Wang L, Guo X. KAI1/CD82 suppresses hepatocyte growth factor-induced migration of hepatoma cells via upregulation of Sprouty2. ACTA ACUST UNITED AC 2008; 51:648-54. [PMID: 18622748 DOI: 10.1007/s11427-008-0086-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2007] [Accepted: 05/19/2008] [Indexed: 12/21/2022]
Abstract
We conducted a study concerning the suppressive mechanism of KAI1/CD82 on hepatoma cell metastasis. Hepatocyte growth factor (HGF) induces the migration of hepatoma cells through activation of cellular sphingosine kinase 1 (SphK1). Adenovirus-mediated gene transfer of KAI1 (Ad-KAI1) downregulates the SphK1 expression and suppresses the HGF-induced migration of SMMC-7721 human hepatocellcular carcinoma cells. Overexpression of KAI1/CD82 significantly elevates Sprouty2 at the protein level. Ablation of Sprouty2 with RNA interference can block the KAI1/CD82-induced suppression of hepatoma cell migration and downregulation of SphK1 expression. It is demonstrated that KAI1/CD82 suppresses HGF-induced migration of hepatoma cells via upregulation of Sprouty2.
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Affiliation(s)
- Zhenbin Mu
- State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
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45
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Yamada M, Sumida Y, Fujibayashi A, Fukaguchi K, Sanzen N, Nishiuchi R, Sekiguchi K. The tetraspanin CD151 regulates cell morphology and intracellular signaling on laminin-511. FEBS J 2008; 275:3335-51. [DOI: 10.1111/j.1742-4658.2008.06481.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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46
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Choi S, Oh SR, Lee SA, Lee SY, Ahn K, Lee HK, Lee JW. Regulation of TM4SF5-mediated tumorigenesis through induction of cell detachment and death by tiarellic acid. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2008; 1783:1632-41. [PMID: 18501196 DOI: 10.1016/j.bbamcr.2008.04.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2007] [Revised: 04/10/2008] [Accepted: 04/15/2008] [Indexed: 01/28/2023]
Abstract
mRNA for four-transmembrane L6 family member 5 (TM4SF5), a homolog of tumor antigen L6, was previously shown to be highly expressed in diverse tumors. We recently found that human hepatocarcinoma tissues also overexpressed TM4SF5 protein, in comparison to normal liver tissues. We also found that tiarellic acid (TA) caused cell detachment-related apoptosis in cells expressing endogenous or stably-overexpressing TM4SF5. When cells expressing TM4SF5 were treated with TA, we observed reduced phosphorylation of focal adhesion kinase, paxillin, and p130Cas, but not c-Src. TA treatment also caused focal adhesion loss and reduced cell adhesion, and increased the numbers of floating cells and apoptotic cells. These effects were blocked by overexpression of focal adhesion molecules, suggesting that treatment with TA mediates anoikis of TM4SF5-expressing cells. However, TM4SF5-null cells were not affected by TA, indicating that these effects occur specifically in TM4SF5-positive cells. TA administration reduced tumor formation in nude mice injected with TM4SF5-expressing cells, presumably through increased apoptosis in TM4SF5-positive tumors. These observations indicate that TM4SF5-positive tumorigenesis can be inhibited by TA via induction of cell detachment-related apoptosis, and suggest that TA may be developed as a putative therapeutic reagent against TM4SF5-positive tumorigenesis.
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Affiliation(s)
- Suyong Choi
- Cancer Research Institute, College of Medicine, Seoul National University, Seoul 110-799, Korea
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47
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Lekishvili T, Fromm E, Mujoomdar M, Berditchevski F. The tumour-associated antigen L6 (L6-Ag) is recruited to the tetraspanin-enriched microdomains: implication for tumour cell motility. J Cell Sci 2008; 121:685-94. [PMID: 18270265 DOI: 10.1242/jcs.020347] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Tumour-associated antigen L6 (L6-Ag, also known as TM4SF1) regulates tumour cell motility and invasiveness. We found that L6-Ag is abundant on the plasma membrane and on intracellular vesicles, on which it is co-localised with the markers for late endosomal/lysosomal compartments, including Lamp1/Lamp2 proteins and LBPA. Antibody internalisation and live-imaging experiments suggested that L6-Ag is targeted to late endocytic organelles (LEO) predominantly via a biosynthetic pathway. Mapping experiments showed that the presence of transmembrane regions is sufficient for directing L6-Ag to LEO. On the plasma membrane, L6-Ag is associated with tetraspanin-enriched microdomains (TERM). All three predicted cytoplasmic regions of L6-Ag are crucial for the effective recruitment of the protein to TERM. Recruitment to TERM correlated with the pro-migratory activity of L6-Ag. Depletion of L6-Ag with siRNA has a selective effect on the surface expression of tetraspanins CD63 and CD82. By contrast, the expression levels of other tetraspanins and beta1 integrins was not affected. We found that L6-Ag is ubiquitylated and that ubiquitylation is essential for its function in cell migration. These data suggest that L6-Ag influences cell motility via TERM by regulating the surface presentation and endocytosis of some of their components.
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Affiliation(s)
- Tamara Lekishvili
- Cancer Research UK Institute for Cancer Studies, The University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
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48
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Kotha J, Longhurst C, Appling W, Jennings LK. Tetraspanin CD9 regulates beta 1 integrin activation and enhances cell motility to fibronectin via a PI-3 kinase-dependent pathway. Exp Cell Res 2008; 314:1811-22. [PMID: 18358474 DOI: 10.1016/j.yexcr.2008.01.024] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2007] [Revised: 01/30/2008] [Accepted: 01/31/2008] [Indexed: 02/07/2023]
Abstract
Tetraspanin CD9 regulates cell motility and other adhesive processes in a variety of tissue types. Using transfected Chinese Hamster Ovary cells as our model system, we examined the cellular pathways critical for CD9 promoted cell migration. alpha 5 beta 1 integrin was directly involved as CD9 enhanced migration was abolished by the alpha 5 beta 1 blocking antibody PB1. Furthermore, the ligand mimetic peptide RGDS, significantly upregulated the expression of a beta1 ligand induced binding site (LIBS) demonstrating for the first time that CD9 expression potentiates beta1 integrin high affinity conformation states. CD9 promoted cell motility was significantly blocked by phosphatidylinositol-3 kinase (PI-3K) inhibitors, wortmannin and LY294002, whereas inhibitors targeting protein kinase C or mitogen-activated protein kinase had no effect. PI-3K dominant/negative cDNA transfections confirmed that PI-3K was an essential component. CD9 enhanced the phosphorylation of the PI-3K substrate, Akt, in response to cell adhesion on FN. CD9 expression also upregulated p130Cas phosphorylation and total protein levels; however, p130Cas siRNA knockdown did not alter the motile phenotype. CD9 enhanced migration was also unaffected by serum deprivation suggesting that growth factors were not critical. Our studies demonstrate that CD9 upregulates beta1 LIBS, and in concert with alpha 5 beta 1, enhances cell motility to FN via a PI-3K dependent mechanism.
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Affiliation(s)
- Jayaprakash Kotha
- Vascular Biology Center of Excellence and the Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
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49
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Lazo PA. Functional implications of tetraspanin proteins in cancer biology. Cancer Sci 2007; 98:1666-77. [PMID: 17727684 PMCID: PMC11159418 DOI: 10.1111/j.1349-7006.2007.00584.x] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2007] [Revised: 06/30/2007] [Accepted: 07/03/2007] [Indexed: 12/25/2022] Open
Abstract
Human tetraspanin proteins are a group of 33 highly hydrophobic membrane proteins that can form complexes in cholesterol-rich microdomains, distinct from lipid rafts, on the cell surface in a dynamic and reversible way. These complexes are composed of a core of several tetraspanin proteins that organize other membrane proteins such as integrins, human leukocyte antigen (HLA) antigens and some growth factor receptors. Although most tetraspanin proteins have been studied individually, tetraspanin proteins and their complexes can have effects on cellular adhesion and motility, interactions with stroma or affect signaling by growth factors, and for most of them no ligand has been identified. Functionally these proteins have been mostly studied in cells of lymphoid lineage, but they are present in all cell types. Data is also available for some tumors, where some tetraspanins have been identified as metastasis suppressors, but their significance is still not clear. Some of their implications in tumor biology and the areas that deserve further study are outlined.
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Affiliation(s)
- Pedro A Lazo
- Programa de Oncología Translacional, Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Salamanca, E-37007, Spain.
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50
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Liu L, He B, Liu WM, Zhou D, Cox JV, Zhang XA. Tetraspanin CD151 promotes cell migration by regulating integrin trafficking. J Biol Chem 2007; 282:31631-42. [PMID: 17716972 DOI: 10.1074/jbc.m701165200] [Citation(s) in RCA: 105] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Regulation of cell migration is an important feature of tetraspanin CD151. Although it is well established that CD151 physically associates with integrins, the mechanism by which CD151 regulates integrin-dependent cell migration is basically unknown. Given the fact that CD151 is localized in both the plasma membrane and intracellular vesicles, we found that CD151 and its associated alpha3beta1, alpha5beta1, and alpha6beta1 integrins undergo endocytosis and accumulate in the same intracellular vesicular compartments. CD151 contains a YRSL sequence, a YXXvarphi type of endocytosis/sorting motif, in its C-terminal cytoplasmic domain. Mutation of this motif markedly attenuated CD151 internalization. The loss of CD151 trafficking completely abrogated CD151-promoted cell migration on extracellular matrices such as laminin and diminished the internalization of its associated integrins, indicating a critical role for integrin trafficking in regulating cell motility. In conclusion, the YXXvarphi motif-mediated internalization of CD151 promotes integrin-dependent cell migration by modulating the endocytosis and/or vesicular trafficking of its associated integrins.
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Affiliation(s)
- Li Liu
- Vascular Biology Center, Cancer Institute, Department of Medicine and Department of Molecular Science, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
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