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Yang KF, Zhang JY, Feng M, Yao K, Liu YY, Zhou MS, Jia H. Secretase promotes AD progression: simultaneously cleave Notch and APP. Front Aging Neurosci 2024; 16:1445470. [PMID: 39634655 PMCID: PMC11615878 DOI: 10.3389/fnagi.2024.1445470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 10/31/2024] [Indexed: 12/07/2024] Open
Abstract
Alzheimer's disease (AD) involves complex pathological mechanisms. Secretases include membrane protein extracellular structural domain proteases and intramembrane proteases that cleave the topology to type I or type II. Secretases can effectively regulate the activation of Notch and amyloid precursor protein (APP), key factors in the progression of AD and cancer. This article systematically summarizes the intracellular localization, cleavage sites and products, and biological functions of six subtypes of secretases (α-secretase, β-secretase, γ-secretase, δ-secretase, ε-secretase, and η-secretase), and for the first time, elucidates the commonalities and differences between these subtypes of secretases. We found that each subtype of secretase primarily cleaves APP and Notch as substrates, regulating Aβ levels through APP cleavage to impact the progression of AD, while also cleaving Notch receptors to affect cancer progression. Finally, we review the chemical structures, indications, and research stages of various secretase inhibitors, emphasizing the promising development of secretase inhibitors in the fields of cancer and AD.
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Affiliation(s)
- Ke-Fan Yang
- Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Shenyang Medical College, Shenyang, China
| | - Jing-Yi Zhang
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Mei Feng
- Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Shenyang Medical College, Shenyang, China
| | - Kuo Yao
- Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Shenyang Medical College, Shenyang, China
| | - Yue-Yang Liu
- Science and Experimental Research Center of Shenyang Medical College, Shenyang, Liaoning, China
| | - Ming-Sheng Zhou
- Science and Experimental Research Center of Shenyang Medical College, Shenyang, Liaoning, China
| | - Hui Jia
- Science and Experimental Research Center of Shenyang Medical College, Shenyang, Liaoning, China
- School of Traditional Chinese Medicine, Shenyang Medical College, Shenyang, Liaoning, China
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Dorta S, Alexandre-Silva V, Popolin CP, de Sousa DB, Grigoli MM, Pelegrini LNDC, Manzine PR, Camins A, Marcello E, Endres K, Cominetti MR. ADAM10 isoforms: Optimizing usage of antibodies based on protein regulation, structural features, biological activity and clinical relevance to Alzheimer's disease. Ageing Res Rev 2024; 101:102464. [PMID: 39173916 DOI: 10.1016/j.arr.2024.102464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/21/2024] [Accepted: 08/16/2024] [Indexed: 08/24/2024]
Abstract
A Disintegrin and Metalloproteinase 10 (ADAM10) is a crucial transmembrane protein involved in diverse cellular processes, including cell adhesion, migration, and proteolysis. ADAM10's ability to cleave over 100 substrates underscores its significance in physiological and pathological contexts, particularly in Alzheimer's disease (AD). This review comprehensively examines ADAM10's multifaceted roles, highlighting its critical function in the non-amyloidogenic processing of the amyloid precursor protein (APP), which mitigates amyloid beta (Aβ) production, a critical factor in AD development. We summarize the regulation of ADAM10 at multiple levels: transcriptional, translational, and post-translational, revealing the complexity and responsiveness of its expression to various cellular signals. A standardized nomenclature for ADAM10 isoforms is proposed to improve clarity and consistency in research, facilitating better comparison and replication of findings across studies. We address the challenges in detecting ADAM10 isoforms using antibodies, advocating for standardized detection protocols to resolve discrepancies in results from different biological matrices. By highlighting these issues, this review underscores the potential of ADAM10 as a biomarker for early diagnosis and a therapeutic target in AD. By consolidating current knowledge on ADAM10's regulation and function, we aim to provide insights that will guide future research and therapeutic strategies in the AD context.
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Affiliation(s)
- Sabrina Dorta
- Department of Gerontology, Federal University of São Carlos, São Carlos, SP, Brazil
| | | | | | | | | | | | | | - Antoni Camins
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Institute of Neurosciences, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Elena Marcello
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, Milan, Italy
| | - Kristina Endres
- Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Marcia Regina Cominetti
- Department of Gerontology, Federal University of São Carlos, São Carlos, SP, Brazil; Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
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Rosenbaum D, Saftig P. New insights into the function and pathophysiology of the ectodomain sheddase A Disintegrin And Metalloproteinase 10 (ADAM10). FEBS J 2024; 291:2733-2766. [PMID: 37218105 DOI: 10.1111/febs.16870] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/11/2023] [Accepted: 05/19/2023] [Indexed: 05/24/2023]
Abstract
The 'A Disintegrin And Metalloproteinase 10' (ADAM10) has gained considerable attention due to its discovery as an 'α-secretase' involved in the nonamyloidogenic processing of the amyloid precursor protein, thereby possibly preventing the excessive generation of the amyloid beta peptide, which is associated with the pathogenesis of Alzheimer's disease. ADAM10 was found to exert many additional functions, cleaving about 100 different membrane proteins. ADAM10 is involved in many pathophysiological conditions, ranging from cancer and autoimmune disorders to neurodegeneration and inflammation. ADAM10 cleaves its substrates close to the plasma membrane, a process referred to as ectodomain shedding. This is a central step in the modulation of the functions of cell adhesion proteins and cell surface receptors. ADAM10 activity is controlled by transcriptional and post-translational events. The interaction of ADAM10 with tetraspanins and the way they functionally and structurally depend on each other is another topic of interest. In this review, we will summarize findings on how ADAM10 is regulated and what is known about the biology of the protease. We will focus on novel aspects of the molecular biology and pathophysiology of ADAM10 that were previously poorly covered, such as the role of ADAM10 on extracellular vesicles, its contribution to virus entry, and its involvement in cardiac disease, cancer, inflammation, and immune regulation. ADAM10 has emerged as a regulator controlling cell surface proteins during development and in adult life. Its involvement in disease states suggests that ADAM10 may be exploited as a therapeutic target to treat conditions associated with a dysfunctional proteolytic activity.
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Affiliation(s)
- David Rosenbaum
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Germany
| | - Paul Saftig
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Germany
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Erin N, Akdeniz Ö. ADAM10 and Neprilysin level decreases in immune cells of mice bearing metastatic breast carcinoma: Possible role in cancer inflammatory response. Int Immunopharmacol 2024; 127:111384. [PMID: 38141405 DOI: 10.1016/j.intimp.2023.111384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 12/25/2023]
Abstract
OBJECTIVE AND DESIGN ADAM10 and Neprilysin, proteases, play critical role in inflammatory disease, however their role in cancer immune response is not clear. We here evaluated changes in immune response using an experimental model for breast cancer. MATERIAL AND METHOD Highly metastatic breast cancer cells (4T1-derived) were injected orthotopically (mammary-pad of Balb-c mice) to induce tumors. Changes in enzyme level and activity as well as alterations in inflammatory cytokine release in the presence or absence of ADAM10 and NEP activity was determined using specific inhibitors and recombinant proteins. Cytokine response was evaluated using mix leucocyte cultures obtained from control and tumor-bearing mice. ANOVA with Dunnett's posttest was used for statistical analysis. RESULTS ADAM10 and NEP expression was decreased markedly in lymph nodes and spleens of tumor-bearing mice. ADAM10 activity was reduced together with apparent alterations of ADAM10 processing. ADAM10 and NEP activity decreased TNF-α, IL-6 and IFN-ɣ secretion. Suppression of these inflammatory cytokines were more prominent in cultures obtained from control mice demonstrating counteracting factors that are exist in tumor-bearing mice. CONCLUSION Loss of ADAM10 and NEP activity in immune cells during breast cancer metastasis might be one of the main factors involved in induction of chronic inflammation by tumors.
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Affiliation(s)
- Nuray Erin
- Akdeniz University, School of Medicine, Department of Medical Pharmacology, Antalya 07070, Turkiye.
| | - Özlem Akdeniz
- Akdeniz University, School of Medicine, Department of Medical Pharmacology, Antalya 07070, Turkiye
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Leinung N, Mentrup T, Patel M, Gallagher T, Schröder B. Dynamic association of the intramembrane proteases SPPL2a/b and their substrates with tetraspanin-enriched microdomains. iScience 2023; 26:107819. [PMID: 37736044 PMCID: PMC10509304 DOI: 10.1016/j.isci.2023.107819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 07/21/2023] [Accepted: 08/31/2023] [Indexed: 09/23/2023] Open
Abstract
Signal peptide peptidase-like 2a and b (SPPL2a/b) are aspartyl intramembrane proteases and cleave tail-anchored proteins as well as N-terminal fragments (NTFs) derived from type II-oriented transmembrane proteins. How these proteases recruit substrates and cleavage is regulated, is still incompletely understood. We found that SPPL2a/b localize to detergent-resistant membrane (DRM) domains with the characteristics of tetraspanin-enriched microdomains (TEMs). Based on this, association with several tetraspanins was evaluated. We demonstrate that not only SPPL2a/b but also their substrates tumor necrosis factor (TNF) and CD74 associate with tetraspanins like CD9, CD81, and CD82 and/or TEMs and analyze the stability of these complexes in different detergents. CD9 and CD81 deficiency has protease- and substrate-selective effects on SPPL2a/b function. Our findings suggest that reciprocal interactions with tetraspanins may assist protease-substrate encounters of SPPL2a/b within the membrane. Beyond SPP/SPPL proteases, this supports previous concepts that tetraspanins facilitate membrane-embedded proteolytic processes.
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Affiliation(s)
- Nadja Leinung
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany
| | - Torben Mentrup
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany
| | - Mehul Patel
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany
| | - Tom Gallagher
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL, USA
| | - Bernd Schröder
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany
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Tan Z, Li W, Cheng X, Zhu Q, Zhang X. Non-Coding RNAs in the Regulation of Hippocampal Neurogenesis and Potential Treatment Targets for Related Disorders. Biomolecules 2022; 13:biom13010018. [PMID: 36671403 PMCID: PMC9855933 DOI: 10.3390/biom13010018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/17/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
Non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, circRNAs, and piRNAs, do not encode proteins. Nonetheless, they have critical roles in a variety of cellular activities-such as development, neurogenesis, degeneration, and the response to injury to the nervous system-via protein translation, RNA splicing, gene activation, silencing, modifications, and editing; thus, they may serve as potential targets for disease treatment. The activity of adult neural stem cells (NSCs) in the subgranular zone of the hippocampal dentate gyrus critically influences hippocampal function, including learning, memory, and emotion. ncRNAs have been shown to be involved in the regulation of hippocampal neurogenesis, including proliferation, differentiation, and migration of NSCs and synapse formation. The interaction among ncRNAs is complex and diverse and has become a major topic within the life science. This review outlines advances in research on the roles of ncRNAs in modulating NSC bioactivity in the hippocampus and discusses their potential applications in the treatment of illnesses affecting the hippocampus.
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Affiliation(s)
- Zhengye Tan
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
| | - Wen Li
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
| | - Xiang Cheng
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
| | - Qing Zhu
- School of Pharmacy, Nantong University, Nantong 226001, China
- Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong 226001, China
| | - Xinhua Zhang
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
- Central Lab, Yancheng Third People’s Hospital, The Sixth Affiliated Hospital of Nantong University, Yancheng 224001, China
- Correspondence:
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Tetraspanin 8 Subfamily Members Regulate Substrate-Specificity of a Disintegrin and Metalloprotease 17. Cells 2022; 11:cells11172683. [PMID: 36078095 PMCID: PMC9454446 DOI: 10.3390/cells11172683] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/09/2022] [Indexed: 12/04/2022] Open
Abstract
Ectodomain shedding is an irreversible process to regulate inter- and intracellular signaling. Members of the a disintegrin and metalloprotease (ADAM) family are major mediators of ectodomain shedding. ADAM17 is involved in the processing of multiple substrates including tumor necrosis factor (TNF) α and EGF receptor ligands. Substrates of ADAM17 are selectively processed depending on stimulus and cellular context. However, it still remains largely elusive how substrate selectivity of ADAM17 is regulated. Tetraspanins (Tspan) are multi-membrane-passing proteins that are involved in the organization of plasma membrane micro-domains and diverse biological processes. Closely related members of the Tspan8 subfamily, including CD9, CD81 and Tspan8, are associated with cancer and metastasis. Here, we show that Tspan8 subfamily members use different strategies to regulate ADAM17 substrate selectivity. We demonstrate that in particular Tspan8 associates with both ADAM17 and TNF α and promotes ADAM17-mediated TNF α release through recruitment of ADAM17 into Tspan-enriched micro-domains. Yet, processing of other ADAM17 substrates is not altered by Tspan8. We, therefore, propose that Tspan8 contributes to tumorigenesis through enhanced ADAM17-mediated TNF α release and a resulting increase in tissue inflammation.
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Shin Y, Jo KS, Shin M, Lee D, Yeo H, Song Y, Kang SW. Role of redox-sensitive catalytic interaction with ADAM10 in mutant-selective extracellular shedding of prion protein. Redox Biol 2022; 56:102456. [PMID: 36041363 PMCID: PMC9440079 DOI: 10.1016/j.redox.2022.102456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/21/2022] [Accepted: 08/22/2022] [Indexed: 12/01/2022] Open
Abstract
Misfolded glycosylphosphatidylinositol-anchored prion protein (PrP) is primarily degraded in lysosomes but is often rapidly removed from the cell surface before endocytosis in a preemptive manner. However, this mechanism is poorly understood. In this study, we discovered a disease-causing prion mutation (Q212P) that exceptionally promoted the extracellular release of PrP. Spatiotemporal analyses combined with genome editing identified the role of sheddase ADAM10 in Q212P shedding from the cell surface. ADAM10 was observed to catalytically interacts with Q212P but non-catalytically with wild-type PrP (wtPrP). This intrinsic difference in the interaction of ADAM10 between Q212P and wtPrP allowed Q212P to selectively access the sheddase activity of ADAM10 in a redox-sensitive manner. In addition, redox perturbation instigated the latent misfolding propensity of Q212P and disrupted the catalytic interaction between PrP and ADAM10, resulting in the accumulation of misfolded PrP on the cell surface. Upon recovery, active ADAM10 was able to reversibly release the surface Q212P. However, it might prove detrimental if unregulated resulting in unexpected proteotoxicity. This study provides a molecular basis of the mutant-selective shedding of PrP by demonstrating the catalytic interaction of ADAM10 with Q212P.
Pathogenic Q212P mutation provides a unique pattern of PrP metabolism. Q212P mutation promotes the extracellular release of surface PrP. Q212P shedding is catalyzed by ADAM10. ADAM10-mediated Q212P shedding is redox-sensitive.
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Affiliation(s)
- Yejin Shin
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea
| | - Kang-Sug Jo
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea
| | - Minseok Shin
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea
| | - Duri Lee
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea
| | - Hyejin Yeo
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea
| | - Youngsup Song
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea; Asan Institute of Life Sciences, Asan Medical Center, Seoul, Republic of Korea
| | - Sang-Wook Kang
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea; Asan Institute of Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
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The transmembrane domain of the amyloid precursor protein is required for anti-amyloidogenic processing by α-secretase ADAM10. J Biol Chem 2022; 298:101911. [PMID: 35398353 PMCID: PMC9127328 DOI: 10.1016/j.jbc.2022.101911] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 03/26/2022] [Accepted: 03/29/2022] [Indexed: 11/24/2022] Open
Abstract
Neurotoxic amyloid β-peptides (Aβ) are thought to be a causative agent of Alzheimer's disease in humans. The production of Aβ from amyloid precursor protein (APP) could be diminished by enhancing α-processing; however, the physical interactions between APP and α-secretases are not well understood. In this study, we employed super-resolution light microscopy to examine in cell-free plasma membranes the abundance and association of APP and α-secretases ADAM10 and ADAM17. We found that both secretase molecules localize similarly closely to APP (within ≤ 50 nm). However, when cross-linking APP with antibodies directed against the GFP-tag of APP, in confocal microscopy we observed that only ADAM10 co-aggregated with APP. Furthermore, we mapped the involved protein domain by using APP variants with an exchanged transmembrane segment or lacking cytoplasmic/extracellular domains. We identified that APP's transmembrane domain is required for association with α-secretases and, as analysed by Western Blot, for α-processing. We propose that the APP transmembrane domain interacts either directly or indirectly with ADAM10, but not with ADAM17, explaining the dominant role of ADAM10 in α-processing of APP. Further understanding of this interaction may facilitate the development of a therapeutic strategy based on promoting APP cleavage by α-secretases.
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Becic A, Leifeld J, Shaukat J, Hollmann M. Tetraspanins as Potential Modulators of Glutamatergic Synaptic Function. Front Mol Neurosci 2022; 14:801882. [PMID: 35046772 PMCID: PMC8761850 DOI: 10.3389/fnmol.2021.801882] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/07/2021] [Indexed: 12/16/2022] Open
Abstract
Tetraspanins (Tspans) comprise a membrane protein family structurally defined by four transmembrane domains and intracellular N and C termini that is found in almost all cell types and tissues of eukaryotes. Moreover, they are involved in a bewildering multitude of diverse biological processes such as cell adhesion, motility, protein trafficking, signaling, proliferation, and regulation of the immune system. Beside their physiological roles, they are linked to many pathophysiological phenomena, including tumor progression regulation, HIV-1 replication, diabetes, and hepatitis. Tetraspanins are involved in the formation of extensive protein networks, through interactions not only with themselves but also with numerous other specific proteins, including regulatory proteins in the central nervous system (CNS). Interestingly, recent studies showed that Tspan7 impacts dendritic spine formation, glutamatergic synaptic transmission and plasticity, and that Tspan6 is correlated with epilepsy and intellectual disability (formerly known as mental retardation), highlighting the importance of particular tetraspanins and their involvement in critical processes in the CNS. In this review, we summarize the current knowledge of tetraspanin functions in the brain, with a particular focus on their impact on glutamatergic neurotransmission. In addition, we compare available resolved structures of tetraspanin family members to those of auxiliary proteins of glutamate receptors that are known for their modulatory effects.
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Rovčanin Dragović I, Popović N, Ždralević M, Radulović L, Vuković T, Marzano F, Tullo A, Radunović M. Inflammation-Related microRNAs-146a and -155 Are Upregulated in Mild Cognitive Impairment Subjects Among Older Age Population in Montenegro. J Alzheimers Dis 2022; 90:625-638. [PMID: 36155522 DOI: 10.3233/jad-220676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Pathological and clinical features of Alzheimer's disease (AD) are in temporal discrepancy and currently accepted clinical tests provide the diagnosis decades after the initial pathophysiological events. In order to enable a more timely detection of AD, research efforts are directed to identification of biomarkers of the early symptomatic stage. Neuroinflammatory signaling pathways and inflammation-related microRNAs (miRNAs) could possibly have a crucial role in AD, making them promising potential biomarkers. OBJECTIVE We examined the expression of circulatory miRNAs with a documented role in AD pathophysiology: miR-29a/b, miR-101, miR-125b, miR-146a, and miR-155 in the plasma of AD patients (AD, n = 12), people with mild cognitive impairment (MCI, n = 9), and normocognitive group (CTRL, n = 18). We hypothesized that these miRNA expression levels could correlate with the level of participants' cognitive decline. METHODS The study participants completed the standardized interview, neurological examination, neuropsychological assessment, and biochemical analyses. miRNA expression levels were assessed by RT-PCR. RESULTS Neurological and laboratory findings could not account for MCI, but miR-146a and -155 were upregulated in the MCI group compared to the control. miR-146a, known to mediate early neuroinflammatory AD events, was also upregulated in the MCI compared to AD group. ROC curve analysis for miRNA-146a showed 77.8% sensitivity and 94.4% specificity and 66.7% sensitivity and 88.9% specificity for miR-155. CONCLUSION Determination of circulatory inflamma-miRs-146a and -155 expression, together with neuropsychological screening, could become a non-invasive tool for detecting individuals with an increased risk for AD, but research on a larger cohort is warranted.
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Affiliation(s)
| | - Nataša Popović
- University of Montenegro, Faculty of Medicine, Podgorica, Montenegro
| | - Maša Ždralević
- University of Montenegro, Faculty of Medicine, Podgorica, Montenegro
| | - Ljiljana Radulović
- Clinical Center of Montenegro, Department of Neurology, Podgorica, Montenegro
| | - Tijana Vuković
- Clinical Center of Montenegro, Department of Neurology, Podgorica, Montenegro
| | - Flaviana Marzano
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, CNR, Bari, Italy
| | - Apollonia Tullo
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, CNR, Bari, Italy
| | - Miodrag Radunović
- University of Montenegro, Faculty of Medicine, Podgorica, Montenegro
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Nakamura M, Li Y, Choi BR, Matas-Rico E, Troncoso J, Takahashi C, Sockanathan S. GDE2-RECK controls ADAM10 α-secretase-mediated cleavage of amyloid precursor protein. Sci Transl Med 2021; 13:13/585/eabe6178. [PMID: 33731436 DOI: 10.1126/scitranslmed.abe6178] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/17/2020] [Indexed: 12/11/2022]
Abstract
A disintegrin and metalloprotease 10 (ADAM10) is the α-secretase for amyloid precursor protein (APP). ADAM10 cleaves APP to generate neuroprotective soluble APPα (sAPPα), which precludes the generation of Aβ, a defining feature of Alzheimer's disease (AD) pathophysiology. Reduced ADAM10 activity is implicated in AD, but the mechanisms mediating ADAM10 modulation are unclear. We find that the plasma membrane enzyme glycerophosphodiester phosphodiesterase 2 (GDE2) stimulates ADAM10 APP cleavage by shedding and inactivating reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a glycosylphosphatidylinositol (GPI)-anchored inhibitor of ADAM10. In AD, membrane-tethered RECK is highly elevated and GDE2 is abnormally sequestered inside neurons. Genetic ablation of GDE2 phenocopies increased membrane RECK in AD, which is causal for reduced sAPPα, increased Aβ, and synaptic protein loss. RECK reduction restores the balance of APP processing and rescues synaptic protein deficits. These studies identify GDE2 control of RECK surface activity as essential for ADAM10 α-secretase function and physiological APP processing. Moreover, our results suggest the involvement of the GDE2-RECK-ADAM10 pathway in AD pathophysiology and highlight RECK as a potential target for therapeutic development.
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Affiliation(s)
- Mai Nakamura
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N Wolfe Street, PCTB 1004, Baltimore, MD 21205, USA
| | - Yuhan Li
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N Wolfe Street, PCTB 1004, Baltimore, MD 21205, USA
| | - Bo-Ran Choi
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N Wolfe Street, PCTB 1004, Baltimore, MD 21205, USA
| | - Elisa Matas-Rico
- Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan, CX 1066 Amsterdam, Netherlands
| | - Juan Troncoso
- Department of Neurology, Department of Pathology, Johns Hopkins University School of Medicine, 600 N Wolfe Street, Baltimore, MD 21205, USA
| | - Chiaki Takahashi
- Cancer Research Institute, Kanazawa University, Kakuma-Cho, Kanazawa City 920-1192, Japan
| | - Shanthini Sockanathan
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N Wolfe Street, PCTB 1004, Baltimore, MD 21205, USA.
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Trop-2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis. Neoplasia 2021; 23:415-428. [PMID: 33839455 PMCID: PMC8042651 DOI: 10.1016/j.neo.2021.03.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 03/10/2021] [Accepted: 03/12/2021] [Indexed: 12/22/2022] Open
Abstract
Trop-2 is a transmembrane signal transducer that can induce cancer growth. Using antibody targeting and N-terminal Edman degradation, we show here that Trop-2 undergoes cleavage in the first thyroglobulin domain loop of its extracellular region, between residues R87 and T88. Molecular modeling indicated that this cleavage induces a profound rearrangement of the Trop-2 structure, which suggested a deep impact on its biological function. No Trop-2 cleavage was detected in normal human tissues, whereas most tumors showed Trop-2 cleavage, including skin, ovary, colon, and breast cancers. Coimmunoprecipitation and mass spectrometry analysis revealed that ADAM10 physically interacts with Trop-2. Immunofluorescence/confocal time-lapse microscopy revealed that the two molecules broadly colocalize at the cell membrane. We show that ADAM10 inhibitors, siRNAs and shRNAs abolish the processing of Trop-2, which indicates that ADAM10 is an effector protease. Proteolysis of Trop-2 at R87-T88 triggered cancer cell growth both in vitro and in vivo. A corresponding role was shown for metastatic spreading of colon cancer, as the R87A-T88A Trop-2 mutant abolished xenotransplant metastatic dissemination. Activatory proteolysis of Trop-2 was recapitulated in primary human breast cancers. Together with the prognostic impact of Trop-2 and ADAM10 on cancers of the skin, ovary, colon, lung, and pancreas, these data indicate a driving role of this activatory cleavage of Trop-2 on malignant progression of tumors.
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14
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Huang J, Ma Y, Wei S, Pan B, Qi Y, Hou Y, Meng Q, Zhou G, Han H. Dynamic changes in the global transcriptome of bovine germinal vesicle oocytes after vitrification followed by in vitro maturation. Reprod Fertil Dev 2019; 30:1298-1313. [PMID: 29661269 DOI: 10.1071/rd17535] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 03/13/2018] [Indexed: 12/11/2022] Open
Abstract
This study was conducted to investigate the effect of vitrification on the dynamics of the global transcriptome in bovine germinal vesicle (GV) oocytes and their in vitro-derived metaphase II (MII) oocytes. The GV oocytes were vitrified using the open-pulled straw method. After warming, GV oocytes and the resulting MII-stage oocytes were cultured in vitro for 2h and 24h respectively and were then collected. The fresh GV oocytes and their in vitro-derived MII oocytes were used as controls. Then, each pool (fresh GV, n=3; vitrified GV, n=4; fresh MII, n=1 and MII derived from vitrified GV, n=2) from the different stages was used for mRNA transcriptome sequencing. The results showed that the in vitro maturation rates of GV oocytes were significantly decreased (32.36% vs 53.14%) after vitrification. Bovine GV oocyte vitrification leads to 12 significantly upregulated and 19 downregulated genes. After culturing in vitro, the vitrification-derived MII oocytes showed 47 significantly upregulated and six downregulated genes when compared with those from fresh GV oocytes. Based on molecular function-gene ontology terms analysis and the Kyoto encyclopaedia of genes (KEGG) pathway database, the differentially expressed genes were associated with the pathways of cell differentiation and mitosis, transcription regulation, regulation of actin cytoskeleton, apoptosis and so on, which potentially result in the lower in vitro development of GV bovine oocytes.
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Affiliation(s)
- Jianwei Huang
- Beijing Key Laboratory for Animal Genetic Improvement, China Agricultural University, Beijing 100193, PR China
| | - YongShun Ma
- Beijing Key Laboratory for Animal Genetic Improvement, China Agricultural University, Beijing 100193, PR China
| | - Shao Wei
- Beijing Key Laboratory for Animal Genetic Improvement, China Agricultural University, Beijing 100193, PR China
| | - Bo Pan
- Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Yu Qi
- Beijing Key Laboratory for Animal Genetic Improvement, China Agricultural University, Beijing 100193, PR China
| | - YunPeng Hou
- State Key Laboratory of AgroBiotechnology, China Agricultural University, Beijing 100193, PR China
| | - QingYong Meng
- State Key Laboratory of AgroBiotechnology, China Agricultural University, Beijing 100193, PR China
| | - GuangBin Zhou
- Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, PR China
| | - HongBing Han
- Beijing Key Laboratory for Animal Genetic Improvement, China Agricultural University, Beijing 100193, PR China
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15
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Koo S, Cheley S, Bayley H. Redirecting Pore Assembly of Staphylococcal α-Hemolysin by Protein Engineering. ACS CENTRAL SCIENCE 2019; 5:629-639. [PMID: 31041382 PMCID: PMC6487460 DOI: 10.1021/acscentsci.8b00910] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Indexed: 05/03/2023]
Abstract
α-Hemolysin (αHL), a β-barrel pore-forming toxin (βPFT), is secreted as a water-soluble monomer by Staphylococcus aureus. Upon binding to receptors on target cell membranes, αHL assembles to form heptameric membrane-spanning pores. We have previously engineered αHL to create a protease-activatable toxin that is activated by site-specific proteolysis including by tumor proteases. In this study, we redesigned αHL so that it requires 2-fold activation on target cells through (i) binding to specific receptors, and (ii) extracellular proteolytic cleavage. To assess our strategy, we constructed a fusion protein of αHL with galectin-1 (αHLG1, αHL-Galectin-1 chimera). αHLG1 was cytolytic toward cells that lack a receptor for wild-type αHL. We then constructed protease-activatable mutants of αHLG1 (PAMαHLG1s). PAMαHLG1s were activated by matrix metalloproteinase 2 (MMP-2) and had approximately 50-fold higher cytolytic activity toward MMP-2 overexpressing cells (HT-1080 cells) than toward non-overexpressing cells (HL-60 cells). Our approach provides a novel strategy for tailoring pore-forming toxins for therapeutic applications.
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Affiliation(s)
- Sunwoo Koo
- Department
of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, 8447 Riverside Parkway, Bryan, Texas 77807, United States
- E-mail: . Phone: 1-979-436-0381
| | - Stephen Cheley
- Department
of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, T6G 2E1 Alberta, Canada
| | - Hagan Bayley
- Department
of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield
Road, Oxford, OX1 3TA England, United Kingdom
- E-mail: . Phone: +44 1865 285101
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16
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Carter CJ. Autism genes and the leukocyte transcriptome in autistic toddlers relate to pathogen interactomes, infection and the immune system. A role for excess neurotrophic sAPPα and reduced antimicrobial Aβ. Neurochem Int 2019; 126:36-58. [PMID: 30862493 DOI: 10.1016/j.neuint.2019.03.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 02/22/2019] [Accepted: 03/06/2019] [Indexed: 12/20/2022]
Abstract
Prenatal and early childhood infections have been implicated in autism. Many autism susceptibility genes (206 Autworks genes) are localised in the immune system and are related to immune/infection pathways. They are enriched in the host/pathogen interactomes of 18 separate microbes (bacteria/viruses and fungi) and to the genes regulated by bacterial toxins, mycotoxins and Toll-like receptor ligands. This enrichment was also observed for misregulated genes from a microarray study of leukocytes from autistic toddlers. The upregulated genes from this leukocyte study also matched the expression profiles in response to numerous infectious agents from the Broad Institute molecular signatures database. They also matched genes related to sudden infant death syndrome and autism comorbid conditions (autoimmune disease, systemic lupus erythematosus, diabetes, epilepsy and cardiomyopathy) as well as to estrogen and thyrotropin responses and to those upregulated by different types of stressors including oxidative stress, hypoxia, endoplasmic reticulum stress, ultraviolet radiation or 2,4-dinitrofluorobenzene, a hapten used to develop allergic skin reactions in animal models. The oxidative/integrated stress response is also upregulated in the autism brain and may contribute to myelination problems. There was also a marked similarity between the expression signatures of autism and Alzheimer's disease, and 44 shared autism/Alzheimer's disease genes are almost exclusively expressed in the blood-brain barrier. However, in contrast to Alzheimer's disease, levels of the antimicrobial peptide beta-amyloid are decreased and the levels of the neurotrophic/myelinotrophic soluble APP alpha are increased in autism, together with an increased activity of α-secretase. sAPPα induces an increase in glutamatergic and a decrease in GABA-ergic synapses creating and excitatory/inhibitory imbalance that has also been observed in autism. A literature survey showed that multiple autism genes converge on APP processing and that many are able to increase sAPPalpha at the expense of beta-amyloid production. A genetically programmed tilt of this axis towards an overproduction of neurotrophic/gliotrophic sAPPalpha and underproduction of antimicrobial beta-amyloid may explain the brain overgrowth and myelination dysfunction, as well as the involvement of pathogens in autism.
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Affiliation(s)
- C J Carter
- PolygenicPathways, 41C Marina, Saint Leonard's on Sea, TN38 0BU, East Sussex, UK.
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17
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Zhao K, Wang Z, Hackert T, Pitzer C, Zöller M. Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression. J Exp Clin Cancer Res 2018; 37:312. [PMID: 30541597 PMCID: PMC6292129 DOI: 10.1186/s13046-018-0961-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 11/14/2018] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The tetraspanins Tspan8 and CD151 promote metastasis, exosomes (Exo) being suggested to be important in the crosstalk between tumor and host. The contribution of Tspan8 and CD151 to host versus tumor-derived exosome (TEX) activities being not defined, we approached the questions using 3-methylcholanthrene-induced (MCA) tumors from wt, Tspan8ko, CD151ko and Tspan8/CD151 (db)ko mice, implanted into tetraspanin-competent and deficient hosts. METHODS Tumor growth and dissemination, hematopoiesis and angiogenesis were surveyed in wild type (wt), Tspan8ko, CD151ko and dbko mice bearing tetraspanin-competent and -deficient MCA tumors. In vitro studies using tumor cells, bone marrow cells (BMC) and endothelial cells (EC) elaborated the mechanism of serum (s)Exo- and TEX-induced target modulation. RESULTS Tumors grew in autochthonous and syngeneic hosts differing in Tspan8- and/or CD151-competence. However, Tspan8ko- and/or CD151ko-tumor cell dissemination and settlement in metastatic organs was significantly reduced in the autochthonous host, and less severely in the wt-host. Impaired wt-MCA tumor dissemination in the ko-host confirmed a contribution of host- and tumor-Tspan8/-CD151 to tumor cell dissemination, delivery of sExo and TEX being severely impaired by a Tspan8ko/CD151ko. Coculturing tumor cells, BMC and EC with sExo and TEX revealed minor defects in epithelial mesenchymal transition and apoptosis resistance of ko tumors. Strongly reduced migratory and invasive capacity of Tspan8ko/CD151ko-MCA relies on distorted associations with integrins and CAM and missing Tspan8/CD151-promoted recruitment of proteases. The defects, differing between Tspan8ko- and CD151ko-MCA, were rescued by wt-TEX and, less efficiently Tspan8ko- and CD151ko-TEX. Minor defects in hematopoietic progenitor maturation were based on the missing association of hematopoietic growth factors /- receptors with CD151 and, less pronounced, Tspan8. Rescue of impaired angiogenesis in ko mice by wt-sExo and promotion of angiogenesis by TEX depended on the association of Tspan8 and CD151 with GPCR and RTK in EC and tumor cells. CONCLUSIONS Tspan8-/CD151-TEX play central roles in tumor progression. Tspan8-/CD151-sExo and TEX contribute by stimulating angiogenesis. Tspan8 and CD151 fulfill these tasks by associating with function-relevant proteins, the additive impact of Tspan8 and CD151 relying on differences in preferred associations. The distinct Tspan8 and CD151 contributions suggest a blockade of TEX-Tspan8 and -CD151 promising for therapeutic intervention.
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Affiliation(s)
- Kun Zhao
- Pancreas Section, University Hospital of Surgery, Ruprecht-Karls-University, Heidelberg, Germany
| | - Zhe Wang
- Pancreas Section, University Hospital of Surgery, Ruprecht-Karls-University, Heidelberg, Germany
- Present Address: Department of Oncology, First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong, China
| | - Thilo Hackert
- Pancreas Section, University Hospital of Surgery, Ruprecht-Karls-University, Heidelberg, Germany
| | - Claudia Pitzer
- Interdisciplinary Neurobehavioral Core, Institute of Pharmacology, Ruprecht-Karls-University, Heidelberg, Germany
| | - Margot Zöller
- Pancreas Section, University Hospital of Surgery, Ruprecht-Karls-University, Heidelberg, Germany
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18
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Wang X, Pei G. Visualization of Alzheimer's Disease Related α-/β-/γ-Secretase Ternary Complex by Bimolecular Fluorescence Complementation Based Fluorescence Resonance Energy Transfer. Front Mol Neurosci 2018; 11:431. [PMID: 30538620 PMCID: PMC6277482 DOI: 10.3389/fnmol.2018.00431] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 11/05/2018] [Indexed: 11/13/2022] Open
Abstract
The competitive ectodomain shedding of amyloid-β precursor protein (APP) by α-secretase and β-secretase, and the subsequent regulated intramembrane proteolysis by γ-secretase are the key processes in amyloid-β peptides (Aβ) generation. Previous studies indicate that secretases form binary complex and the interactions between secretases take part in substrates processing. However, whether α-, β- and γ-secretase could form ternary complex remains to be explored. Here, we adopted bimolecular fluorescence complementation in combination with fluorescence resonance energy transfer (BiFC-FRET) to visualize the formation of triple secretase complex. We show that the interaction between α-secretase ADAM10 and β-secretase BACE1 could be monitored by BiFC assay and the binding of APP to α-/β-secretase binary complex was revealed by BiFC-FRET. Further, we observed that γ-secretase interacts with α-/β-secretase binary complex, providing evidence that α-, β- and γ-secretase might form a ternary complex. Thus our study extends the interplay among Alzheimer's disease (AD) related α-/β-/γ-secretase.
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Affiliation(s)
- Xin Wang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Gang Pei
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.,School of Life Science and Technology, and The Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, China
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19
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Miya Shaik M, Tamargo IA, Abubakar MB, Kamal MA, Greig NH, Gan SH. The Role of microRNAs in Alzheimer's Disease and Their Therapeutic Potentials. Genes (Basel) 2018; 9:genes9040174. [PMID: 29561798 PMCID: PMC5924516 DOI: 10.3390/genes9040174] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 03/05/2018] [Accepted: 03/05/2018] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are short, endogenous, non-coding RNAs that post-transcriptionally regulate gene expression by base pairing with mRNA targets. Altered miRNA expression profiles have been observed in several diseases, including neurodegeneration. Multiple studies have reported altered expressions of miRNAs in the brains of individuals with Alzheimer’s disease (AD) as compared to those of healthy elderly adults. Some of the miRNAs found to be dysregulated in AD have been reported to correlate with neuropathological changes, including plaque and tangle accumulation, as well as altered expressions of species that are known to be involved in AD pathology. To examine the potentially pathogenic functions of several dysregulated miRNAs in AD, we review the current literature with a focus on the activities of ten miRNAs in biological pathways involved in AD pathogenesis. Comprehensive understandings of the expression profiles and activities of these miRNAs will illuminate their roles as potential therapeutic targets in AD brain and may lead to the discovery of breakthrough treatment strategies for AD.
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Affiliation(s)
- Munvar Miya Shaik
- School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia.
| | - Ian A Tamargo
- Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
| | - Murtala B Abubakar
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, PMB 2254 Sokoto, Nigeria.
| | - Mohammad A Kamal
- Metabolomics and Enzymology Unit, Fundamental and Applied Biology Group, King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia.
| | - Nigel H Greig
- Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
| | - Siew Hua Gan
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor, Malaysia.
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20
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Abstract
As a member of the A Disintegrin And Metalloproteinase (ADAM) family, ADAM10 has been identified as the constitutive α-secretase in the process of amyloid-β protein precursor (AβPP) cleavage and plays a critical role in reducing the generation of the amyloid-β (Aβ) peptides. Recent studies have demonstrated its beneficial role in alleviating the pathologic impairment in Alzheimer's disease (AD) both in vitro and in vivo. However, the role of ADAM10 in AD and the underlying molecular mechanisms are still not well established. Increasing evidence indicates that ADAM10 not only reduces the generation of Aβ but may also affect the pathology of AD through potential mechanisms including reducing tau pathology, maintaining normal synaptic functions, and promoting hippocampal neurogenesis and the homeostasis of neuronal networks. Mechanistically, ADAM10 regulates these functions by interacting with postsynaptic substrates in brain, especially synaptic cell receptors and adhesion molecules. Furthermore, ADAM10 protein in platelets seems to be a promising biomarker for AD diagnosis. This review will summarize the role of ADAM10 in AD and highlight its functions besides its role as the α-secretase in AβPP cleavage. Meanwhile, we will discuss the therapeutic potential of ADAM10 in treating AD.
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Affiliation(s)
- Xiang-Zhen Yuan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Sen Sun
- Qingdao Blood Center, Qingdao, China
| | - Chen-Chen Tan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Jin-Tai Yu
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Lan Tan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
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21
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Hu Z, Hou D, Wang X, You Z, Cao X. TSPAN12 is overexpressed in NSCLC via p53 inhibition and promotes NSCLC cell growth in vitro and in vivo. Onco Targets Ther 2018. [PMID: 29535534 PMCID: PMC5840276 DOI: 10.2147/ott.s155620] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Background Tetraspanin 12 (TSPAN12), a member of the phylogenetically ancient tetraspanin family, is linked to impaired vascularization of the eye called familial exudative vitreoretinopathy, while the functional role of TSPAN12 in lung cancer has not been well characterized. Results In our study, TSPAN12 is able to regulate the growth of non-small-cell lung carcinoma (NSCLC) cells both in vitro and in vivo. TSPAN12 mRNA level was significantly increased in human NSCLC samples compared with their corresponding paracancerous histologic normal tissues. In addition, TSPAN12 expression, which is frequently upregulated in NSCLC, is inversely correlated with p53 expression. Furthermore, the expression levels of TSPAN12 were also increased in three human NSCLC cell lines compared to human bronchial epithelial (16HBE) cells. Then, we studied the effects of TSPAN12 silencing by short hairpin ribonucleic acid on NSCLC cell growth in vitro and tumorigenesis in vivo, along with the effect on the p53 pathway. Knockdown of TSPAN12 in NSCLC cells inhibited cell proliferation and colony formation. In addition, knockdown of TSPAN12 increased apoptosis in NSCLC cells. Mechanistically, TSPAN12 could modulate the expression of p53, p21, and p27 in NSCLC cells. In a tumor xenograft model, TSPAN12 silencing inhibits the tumor growth of H1299 cells. Conclusion Taken together, our results reveal that TSPAN12 plays an important role in NSCLC and is a potential biomarker and a promising target in the treatment of NSCLC.
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Affiliation(s)
- Zhongwu Hu
- Department of Thoracic Surgery, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, China
| | - Daorong Hou
- Key Laboratory of Model Animal Research, Animal Core Facility of Nanjing Medical University, Nanjing, China
| | - Xiaowei Wang
- Department of Medical Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China
| | - Zhenbing You
- Department of Thoracic Surgery, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, China
| | - Xiufeng Cao
- Department of Surgical Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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22
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Idda ML, Munk R, Abdelmohsen K, Gorospe M. Noncoding RNAs in Alzheimer's disease. WILEY INTERDISCIPLINARY REVIEWS. RNA 2018; 9. [PMID: 29327503 PMCID: PMC5847280 DOI: 10.1002/wrna.1463] [Citation(s) in RCA: 142] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 11/24/2017] [Accepted: 11/29/2017] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia among the elderly worldwide. Despite intense efforts to develop drugs for preventing and treating AD, no effective therapies are available as yet, posing a growing burden at the personal, medical, and socioeconomic levels. AD is characterized by the production and aggregation of amyloid β (Aβ) peptides derived from amyloid precursor protein (APP), the presence of hyperphosphorylated microtubule-associated protein Tau (MAPT), and chronic inflammation leading to neuronal loss. Aβ accumulation and hyperphosphorylated Tau are responsible for the main histopathological features of AD, Aβ plaques, and neurofibrillary tangles (NFTs), respectively. However, the full spectrum of molecular factors that contribute to AD pathogenesis is not known. Noncoding (nc)RNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), regulate gene expression at the transcriptional and posttranscriptional levels in various diseases, serving as biomarkers and potential therapeutic targets. There is rising recognition that ncRNAs have been implicated in both the onset and pathogenesis of AD. Here, we review the ncRNAs implicated posttranscriptionally in the main AD pathways and discuss the growing interest in targeting regulatory ncRNAs therapeutically to combat AD pathology. WIREs RNA 2018, 9:e1463. doi: 10.1002/wrna.1463 This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- M Laura Idda
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland
| | - Rachel Munk
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland
| | - Kotb Abdelmohsen
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland
| | - Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland
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23
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Braidy N, Essa MM, Poljak A, Selvaraju S, Al-Adawi S, Manivasagm T, Thenmozhi AJ, Ooi L, Sachdev P, Guillemin GJ. Consumption of pomegranates improves synaptic function in a transgenic mice model of Alzheimer's disease. Oncotarget 2018; 7:64589-64604. [PMID: 27486879 PMCID: PMC5323101 DOI: 10.18632/oncotarget.10905] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 06/17/2016] [Indexed: 01/18/2023] Open
Abstract
Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by extracellular plaques containing abnormal Amyloid Beta (Aβ) aggregates, intracellular neurofibrillary tangles containing hyperphosphorylated tau protein, microglia-dominated neuroinflammation, and impairments in synaptic plasticity underlying cognitive deficits. Therapeutic strategies for the treatment of AD are currently limited. In this study, we investigated the effects of dietary supplementation of 4% pomegranate extract to a standard chow diet on neuroinflammation, and synaptic plasticity in APPsw/Tg2576 mice brain. Treatment with a custom mixed diet (pellets) containing 4% pomegranate for 15 months ameliorated the loss of synaptic structure proteins, namely PSD-95, Munc18-1, and SNAP25, synaptophysin, phosphorylation of Calcium/Calmodulin Dependent Protein Kinase IIα (p-CaMKIIα/ CaMKIIα), and phosphorylation of Cyclic AMP-Response Element Binding Protein (pCREB/CREB), inhibited neuroinflammatory activity, and enhanced autophagy, and activation of the phophoinositide-3-kinase-Akt-mammalian target of rapamycin signaling pathway. These neuroprotective effects were associated with reduced β-site cleavage of Amyloid Precursor Protein in APPsw/Tg2576 mice. Therefore, long-term supplementation with pomegranates can attenuate AD pathology by reducing inflammation, and altering APP-dependent processes.
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Affiliation(s)
- Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Musthafa Mohamed Essa
- Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Al Khoudh, Oman.,Ageing and Dementia Research Group, Sultan Qaboos University, Al Khoudh, Oman
| | - Anne Poljak
- Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia.,College of Medicine and Health Sciences, Sultan Qaboos University, Al Khoudh, Oman
| | - Subash Selvaraju
- Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Al Khoudh, Oman.,Ageing and Dementia Research Group, Sultan Qaboos University, Al Khoudh, Oman
| | - Samir Al-Adawi
- Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Al Khoudh, Oman.,College of Medicine and Health Sciences, Sultan Qaboos University, Al Khoudh, Oman
| | | | | | - Lezanne Ooi
- Illawarra Health and Medical Research Institute, University of Wollongong, NSW, Australia
| | - Perminder Sachdev
- Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia.,Neuropsychiatric Institute, The Prince of Wales Hospital, Sydney, Australia
| | - Gilles J Guillemin
- Neuroinflammation Group, MND and Neurodegenerative Diseases Research Centre, Macquarie University, NSW, Australia
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24
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Álvarez-Fernández SM, Barbariga M, Cannizzaro L, Cannistraci CV, Hurley L, Zanardi A, Conti A, Sanvito F, Innocenzi A, Pecorelli N, Braga M, Alessio M. Serological immune response against ADAM10 pro-domain is associated with favourable prognosis in stage III colorectal cancer patients. Oncotarget 2018; 7:80059-80076. [PMID: 27517630 PMCID: PMC5346771 DOI: 10.18632/oncotarget.11181] [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: 04/12/2016] [Accepted: 07/10/2016] [Indexed: 02/07/2023] Open
Abstract
A humoral immune response against aberrant tumor proteins can be elicited in cancer patients, resulting in the production of auto-antibodies (Abs). By serological proteome analysis we identified the surface membrane protein ADAM10, a metalloproteinase that has a role in epithelial-tumor progression and invasion, as a target of the immune response in colorectal cancer (Crc). A screening carried out on the purified protein using testing cohorts of sera (Crc patients n = 57; control subjects n = 39) and validation cohorts of sera (Crc patients n = 49; control subjects n = 52) indicated that anti-ADAM10 auto-Abs were significantly induced in a large group (74%) of colon cancer patients, in particular in patients at stage II and III of the disease. Interestingly, in Crc patients classified as stage III disease, the presence of anti-ADAM10 auto-Abs in the sera was associated with a favourable follow-up with a significant shifting of the recurrence-free survival median time from 23 to 55 months. Even though the ADAM10 protein was expressed in Crc regardless the presence of auto-Abs, the immature/non-functional isoform of ADAM10 was highly expressed in the tumor of anti-ADAM10-positive patients and was the isoform targeted by the auto-Abs. In conclusion, the presence of anti-ADAM10 auto-Abs seems to reflect the increased tumor expression of the immunogenic immature-ADAM10 in a group of Crc patients, and is associated with a favourable prognosis in patients at stage III of the disease.
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Affiliation(s)
| | - Marco Barbariga
- Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, Milan, Italy.,Translational Neurology group, Wallenberg Neuroscience Center, BMC, Lund, Sweden
| | - Luca Cannizzaro
- Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, Milan, Italy.,Systems Biology Center, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Carlo Vittorio Cannistraci
- Biomedical Cybernetics Group, Biotechnology Center (BIOTEC), Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Germany
| | - Laura Hurley
- Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, Milan, Italy.,Wayne State University, School of Medicine, Cancer Biology PhD Program, Detroit, Michigan, USA
| | - Alan Zanardi
- Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, Milan, Italy
| | - Antonio Conti
- Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, Milan, Italy
| | | | - Anna Innocenzi
- Pathology, IRCCS-San Raffaele Scientific Institute, Milan, Italy
| | - Nicolò Pecorelli
- Department of Surgery, Vita-Salute San Raffaele University, Milan, Italy
| | - Marco Braga
- Department of Surgery, Vita-Salute San Raffaele University, Milan, Italy
| | - Massimo Alessio
- Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, Milan, Italy
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Shimoda M, Khokha R. Metalloproteinases in extracellular vesicles. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017; 1864:1989-2000. [DOI: 10.1016/j.bbamcr.2017.05.027] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 05/27/2017] [Accepted: 05/30/2017] [Indexed: 12/21/2022]
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Scissor sisters: regulation of ADAM10 by the TspanC8 tetraspanins. Biochem Soc Trans 2017; 45:719-730. [PMID: 28620033 PMCID: PMC5473022 DOI: 10.1042/bst20160290] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 02/26/2017] [Accepted: 02/28/2017] [Indexed: 12/20/2022]
Abstract
A disintegrin and metalloprotease 10 (ADAM10) is a ubiquitously expressed transmembrane protein which is essential for embryonic development through activation of Notch proteins. ADAM10 regulates over 40 other transmembrane proteins and acts as a ‘molecular scissor’ by removing their extracellular regions. ADAM10 is also a receptor for α-toxin, a major virulence factor of Staphylococcus aureus. Owing to the importance of its substrates, ADAM10 is a potential therapeutic target for cancer, neurodegenerative diseases such as Alzheimer's and prion diseases, bacterial infection and inflammatory diseases such as heart attack, stroke and asthma. However, targetting ADAM10 is likely to result in toxic side effects. The tetraspanins are a superfamily of 33 four-transmembrane proteins in mammals which interact with and regulate specific partner proteins within membrane nanodomains. Tetraspanins appear to have a cone-shaped structure with a cholesterol-binding cavity, which may enable tetraspanins to undergo cholesterol-regulated conformational change. An emerging paradigm for tetraspanin function is the regulation of ADAM10 by the TspanC8 subgroup of tetraspanins, namely Tspan5, 10, 14, 15, 17 and 33. This review will describe how TspanC8s are required for ADAM10 trafficking from the endoplasmic reticulum and its enzymatic maturation. Moreover, different TspanC8s localise ADAM10 to different subcellular localisations and may cause ADAM10 to adopt distinct conformations and cleavage of distinct substrates. We propose that ADAM10 should now be regarded as six different scissor proteins depending on the interacting TspanC8. Therapeutic targetting of specific TspanC8/ADAM10 complexes could allow ADAM10 targetting in a cell type- or substrate-specific manner, to treat certain diseases while minimising toxicity.
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27
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Regulation of the trafficking and the function of the metalloprotease ADAM10 by tetraspanins. Biochem Soc Trans 2017; 45:937-44. [PMID: 28687716 DOI: 10.1042/bst20160296] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 03/15/2017] [Accepted: 04/03/2017] [Indexed: 12/11/2022]
Abstract
By interacting directly with partner proteins and with one another, tetraspanins organize a network of interactions referred to as the tetraspanin web. ADAM10 (A Disintegrin And Metalloprotease 10), an essential membrane-anchored metalloprotease that cleaves off the ectodomain of a large variety of cell surface proteins including cytokines, adhesion molecules, the precursor of the β-amyloid peptide APP or Notch, has emerged as a major component of the tetraspanin web. Recent studies have shown that ADAM10 associates directly with all members (Tspan5, Tspan10, Tspan14, Tspan15, Tspan17 and Tspan33) of a subgroup of tetraspanins having eight cysteines in the large extracellular domain and referred to as TspanC8. All TspanC8 regulate ADAM10 exit from the endoplasmic reticulum, but differentially regulate its subsequent trafficking and its function, and have notably a different impact on Notch signaling. TspanC8 orthologs in invertebrates also regulate ADAM10 trafficking and Notch signaling. It may be possible to target TspanC8 tetraspanins to modulate in a tissue- or substrate-restricted manner ADAM10 function in pathologies such as cardiovascular diseases, cancer or Alzheimer's disease.
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28
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Termini CM, Gillette JM. Tetraspanins Function as Regulators of Cellular Signaling. Front Cell Dev Biol 2017; 5:34. [PMID: 28428953 PMCID: PMC5382171 DOI: 10.3389/fcell.2017.00034] [Citation(s) in RCA: 194] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 03/22/2017] [Indexed: 01/10/2023] Open
Abstract
Tetraspanins are molecular scaffolds that distribute proteins into highly organized microdomains consisting of adhesion, signaling, and adaptor proteins. Many reports have identified interactions between tetraspanins and signaling molecules, finding unique downstream cellular consequences. In this review, we will explore these interactions as well as the specific cellular responses to signal activation, focusing on tetraspanin regulation of adhesion-mediated (integrins/FAK), receptor-mediated (EGFR, TNF-α, c-Met, c-Kit), and intracellular signaling (PKC, PI4K, β-catenin). Additionally, we will summarize our current understanding for how tetraspanin post-translational modifications (palmitoylation, N-linked glycosylation, and ubiquitination) can regulate signal propagation. Many of the studies outlined in this review suggest that tetraspanins offer a potential therapeutic target to modulate aberrant signal transduction pathways that directly impact a host of cellular behaviors and disease states.
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Affiliation(s)
- Christina M Termini
- Department of Pathology, University of New Mexico Health Sciences CenterAlbuquerque, NM, USA
| | - Jennifer M Gillette
- Department of Pathology, University of New Mexico Health Sciences CenterAlbuquerque, NM, USA
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29
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Millan MJ. Linking deregulation of non-coding RNA to the core pathophysiology of Alzheimer's disease: An integrative review. Prog Neurobiol 2017; 156:1-68. [PMID: 28322921 DOI: 10.1016/j.pneurobio.2017.03.004] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 03/09/2017] [Accepted: 03/09/2017] [Indexed: 02/06/2023]
Abstract
The human genome encodes a vast repertoire of protein non-coding RNAs (ncRNA), some specific to the brain. MicroRNAs, which interfere with the translation of target mRNAs, are of particular interest since their deregulation has been implicated in neurodegenerative disorders like Alzheimer's disease (AD). However, it remains challenging to link the complex body of observations on miRNAs and AD into a coherent framework. Using extensive graphical support, this article discusses how a diverse panoply of miRNAs convergently and divergently impact (and are impacted by) core pathophysiological processes underlying AD: neuroinflammation and oxidative stress; aberrant generation of β-amyloid-42 (Aβ42); anomalies in the production, cleavage and post-translational marking of Tau; impaired clearance of Aβ42 and Tau; perturbation of axonal organisation; disruption of synaptic plasticity; endoplasmic reticulum stress and the unfolded protein response; mitochondrial dysfunction; aberrant induction of cell cycle re-entry; and apoptotic loss of neurons. Intriguingly, some classes of miRNA provoke these cellular anomalies, whereas others act in a counter-regulatory, protective mode. Moreover, changes in levels of certain species of miRNA are a consequence of the above-mentioned anomalies. In addition to miRNAs, circular RNAs, piRNAs, long non-coding RNAs and other types of ncRNA are being increasingly implicated in AD. Overall, a complex mesh of deregulated and multi-tasking ncRNAs reciprocally interacts with core pathophysiological mechanisms underlying AD. Alterations in ncRNAs can be detected in CSF and the circulation as well as the brain and are showing promise as biomarkers, with the ultimate goal clinical exploitation as targets for novel modes of symptomatic and course-altering therapy.
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Affiliation(s)
- Mark J Millan
- Centre for Therapeutic Innovation in Neuropsychiatry, institut de recherche Servier, 125 chemin de ronde, 78290 Croissy sur Seine, France.
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Endres K, Deller T. Regulation of Alpha-Secretase ADAM10 In vitro and In vivo: Genetic, Epigenetic, and Protein-Based Mechanisms. Front Mol Neurosci 2017; 10:56. [PMID: 28367112 PMCID: PMC5355436 DOI: 10.3389/fnmol.2017.00056] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 02/20/2017] [Indexed: 12/21/2022] Open
Abstract
ADAM10 (A Disintegrin and Metalloproteinase 10) has been identified as the major physiological alpha-secretase in neurons, responsible for cleaving APP in a non-amyloidogenic manner. This cleavage results in the production of a neuroprotective APP-derived fragment, APPs-alpha, and an attenuated production of neurotoxic A-beta peptides. An increase in ADAM10 activity shifts the balance of APP processing toward APPs-alpha and protects the brain from amyloid deposition and disease. Thus, increasing ADAM10 activity has been proposed an attractive target for the treatment of neurodegenerative diseases and it appears to be timely to investigate the physiological mechanisms regulating ADAM10 expression. Therefore, in this article, we will (1) review reports on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or protein interactions, (2) describe conditions, which change ADAM10 expression in vitro and in vivo, (3) report how neuronal ADAM10 expression may be regulated in humans, and (4) discuss how this knowledge on the physiological and pathophysiological regulation of ADAM10 may help to preserve or restore brain function.
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Affiliation(s)
- Kristina Endres
- Clinic of Psychiatry and Psychotherapy, University Medical Center Johannes Gutenberg-University Mainz Mainz, Germany
| | - Thomas Deller
- Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt/Main, Germany
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31
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Liu J, Chen C, Li G, Chen D, Zhou Q. Upregulation of TSPAN12 is associated with the colorectal cancer growth and metastasis. Am J Transl Res 2017; 9:812-822. [PMID: 28337310 PMCID: PMC5340717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 01/31/2017] [Indexed: 06/06/2023]
Abstract
Tetraspanin 12 (TSPAN12), as an earliest member of tetraspanin family, has been recently shown to be highly expressed in several malignant tumors, such as lung cancer and breast cancer, which plays an important role in regulating cell proliferation, migration and invasion. However, the functional roles of TSPAN12 in colorectal cancer (CRC) remain largely unclear. In this study, the expression of TSPAN12 was up-regulated compared to that in paracarcinoma tissues. Higher TSPAN12 expression was significantly correlated with TNM stage, tumor size and lymph node metastasis. The vitro functional analysis, including MTT, colony formation, flow cytometry and transwell assays indicated that lentivirus-mediated TSPAN12 knockdown significantly suppressed cell proliferation, migration and invasion, induced cell apoptosis of CRC cells. In addition, knockdown of TSPAN12 remarkably decreased the growth of subcutaneously inoculated tumors in nude mice. Our findings for the first time supported that TSPAN12 might play a positive role in the regulation of CRC cell proliferation, migration and invasion. The inhibition of TSPAN12 may serve as a novel promising therapeutic strategy against human CRC.
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Affiliation(s)
- Jiao Liu
- Department of Critical Care Medicine, Renmin Hospital of Wuhan UniversityWuhan 430060, Hubei Province, China
| | - Chuang Chen
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityWuhan 430060, Hubei Province, China
| | - Guang Li
- Department of Critical Care Medicine, Renmin Hospital of Wuhan UniversityWuhan 430060, Hubei Province, China
| | - Dechang Chen
- Deparment of Emergency and Critical Care Medicine, Shanghai Changzheng Hospital, Second Military Medical UniversityShanghai 200003, China
| | - Qingshan Zhou
- Department of Critical Care Medicine, Renmin Hospital of Wuhan UniversityWuhan 430060, Hubei Province, China
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Abstract
A compelling long-term goal of cancer biology is to understand the crucial players during tumorigenesis in order to develop new interventions. Here, we review how the four non-redundant tissue inhibitors of metalloproteinases (TIMPs) regulate the pericellular proteolysis of a vast range of matrix and cell surface proteins, generating simultaneous effects on tumour architecture and cell signalling. Experimental studies demonstrate the contribution of TIMPs to the majority of cancer hallmarks, and human cancers invariably show TIMP deregulation in the tumour or stroma. Of the four TIMPs, TIMP1 overexpression or TIMP3 silencing is consistently associated with cancer progression or poor patient prognosis. Future efforts will align mouse model systems with changes in TIMPs in patients, will delineate protease-independent TIMP function, will pinpoint therapeutic targets within the TIMP-metalloproteinase-substrate network and will use TIMPs in liquid biopsy samples as biomarkers for cancer prognosis.
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Affiliation(s)
- Hartland W Jackson
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, TMDT 301-13, 101 College Street, Toronto, Ontario, M5G IL7 Canada
- Bodenmiller Laboratory, University of Zürich, Institute for Molecular Life Sciences, Winterthurstrasse 190, 8057 Zürich, Switzerland
| | - Virginie Defamie
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, TMDT 301-13, 101 College Street, Toronto, Ontario, M5G IL7 Canada
| | - Paul Waterhouse
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, TMDT 301-13, 101 College Street, Toronto, Ontario, M5G IL7 Canada
| | - Rama Khokha
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, TMDT 301-13, 101 College Street, Toronto, Ontario, M5G IL7 Canada
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Seipold L, Saftig P. The Emerging Role of Tetraspanins in the Proteolytic Processing of the Amyloid Precursor Protein. Front Mol Neurosci 2016; 9:149. [PMID: 28066176 PMCID: PMC5174118 DOI: 10.3389/fnmol.2016.00149] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 12/05/2016] [Indexed: 12/20/2022] Open
Abstract
Tetraspanins are a family of ubiquitously expressed and conserved proteins, which are characterized by four transmembrane domains and the formation of a short and a large extracellular loop (LEL). Through interaction with other tetraspanins and transmembrane proteins such as growth factors, receptors and integrins, tetraspanins build a wide ranging and membrane spanning protein network. Such tetraspanin-enriched microdomains (TEMs) contribute to the formation and stability of functional signaling complexes involved in cell activation, adhesion, motility, differentiation, and malignancy. There is increasing evidence showing that the tetraspanins also regulate the proteolysis of the amyloid precursor protein (APP) by physically interacting with the APP secretases. CD9, CD63, CD81, Tspan12, Tspan15 are among the tetraspanins involved in the intracellular transport and in the stabilization of the gamma secretase complex or ADAM10 as the major APP alpha secretase. They also directly regulate, most likely in concert with other tetraspanins, the proteolytic function of these membrane embedded enzymes. Despite the knowledge about the interaction of tetraspanins with the secretases not much is known about their physiological role, their importance in Alzheimer's Disease and their exact mode of action. This review aims to summarize the current knowledge and open questions regarding the biology of tetraspanins and the understanding how these proteins interact with APP processing pathways. Ultimately, it will be of interest if tetraspanins are suitable targets for future therapeutical approaches.
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Affiliation(s)
- Lisa Seipold
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel (CAU) Kiel, Germany
| | - Paul Saftig
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel (CAU) Kiel, Germany
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Seipold L, Damme M, Prox J, Rabe B, Kasparek P, Sedlacek R, Altmeppen H, Willem M, Boland B, Glatzel M, Saftig P. Tetraspanin 3: A central endocytic membrane component regulating the expression of ADAM10, presenilin and the amyloid precursor protein. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1864:217-230. [PMID: 27818272 DOI: 10.1016/j.bbamcr.2016.11.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/28/2016] [Accepted: 11/02/2016] [Indexed: 12/31/2022]
Abstract
Despite existing knowledge about the role of the A Disintegrin and Metalloproteinase 10 (ADAM10) as the α-secretase involved in the non-amyloidogenic processing of the amyloid precursor protein (APP) and Notch signalling we have only limited information about its regulation. In this study, we have identified ADAM10 interactors using a split ubiquitin yeast two hybrid approach. Tetraspanin 3 (Tspan3), which is highly expressed in the murine brain and elevated in brains of Alzheimer´s disease (AD) patients, was identified and confirmed to bind ADAM10 by co-immunoprecipitation experiments in mammalian cells in complex with APP and the γ-secretase protease presenilin. Tspan3 expression increased the cell surface levels of its interacting partners and was mainly localized in early and late endosomes. In contrast to the previously described ADAM10-binding tetraspanins, Tspan3 did not affect the endoplasmic reticulum to plasma membrane transport of ADAM10. Heterologous Tspan3 expression significantly increased the appearance of carboxy-terminal cleavage products of ADAM10 and APP, whereas N-cadherin ectodomain shedding appeared unaffected. Inhibiting the endocytosis of Tspan3 by mutating a critical cytoplasmic tyrosine-based internalization motif led to increased surface expression of APP and ADAM10. After its downregulation in neuroblastoma cells and in brains of Tspan3-deficient mice, ADAM10 and APP levels appeared unaltered possibly due to a compensatory increase in the expression of Tspans 5 and 7, respectively. In conclusion, our data suggest that Tspan3 acts in concert with other tetraspanins as a stabilizing factor of active ADAM10, APP and the γ-secretase complex at the plasma membrane and within the endocytic pathway.
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Affiliation(s)
- Lisa Seipold
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
| | - Markus Damme
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
| | - Johannes Prox
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
| | - Björn Rabe
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
| | - Petr Kasparek
- Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases, Division BIOCEV, Institute of Molecular Genetics of the CAS, v. v. i., Vestec, Czech Republic
| | - Radislav Sedlacek
- Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases, Division BIOCEV, Institute of Molecular Genetics of the CAS, v. v. i., Vestec, Czech Republic
| | - Hermann Altmeppen
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Willem
- Biomedical Center, Ludwig-Maximilians-University, 81337 Munich, Germany
| | - Barry Boland
- Department of Pharmacology and Therapeutics, School of Medicine, University College Cork, Cork, Ireland
| | - Markus Glatzel
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Paul Saftig
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
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Erin N, İpekçi T, Akkaya B, Özbudak İH, Baykara M. Changes in expressions of ADAM9, 10, and 17 as well as α-secretase activity in renal cell carcinoma. Urol Oncol 2016; 35:36.e15-36.e22. [PMID: 27692848 DOI: 10.1016/j.urolonc.2016.08.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 08/17/2016] [Accepted: 08/19/2016] [Indexed: 01/10/2023]
Abstract
BACKGROUND ADAM9, 10, and 17 are a class of disintegrins and metallproteinases with α-secretase activity. There are conflicting results regarding the role(s) of ADAM9, 10, and 17 in carcinogenesis, and only a few studies have examined their levels and cellular localization in renal cell carcinoma (RCC). Studies examining changes in α-secretase activity in RCC compared to enzymatic activity of the uninvolved kidney are lacking. METHOD A cross-sectional study was conducted in 56 patients undergoing radical nephrectomy after the diagnosis of RCC. α-Secretase activity was determined using flourogenic substrate in freshly frozen tumor tissues as well as similarly treated tissues from the neighboring kidney. Immunohistochemical analyses of ADAM9, 10, and 17 were also performed. RESULTS α-Secretase activity decreased markedly in all types of RCC as compared to neighboring uninvolved kidney tissue having 5 to 10 times higher levels of α-secretase activity. Although type-dependent variations were observed, tumoral expressions of ADAMs, except for ADAM17, were lower in the tumors compared to that of neighboring tissues, but the changes in α-secretase activity were greater. In RCC tissue, ADAM9 expressions were localized in nuclear and cytoplasmic compartments, whereas ADAM10 and 17 were present predominately in the cytoplasm potentially explaining the markedly decreased enzyme activity. Membranous localization of ADAMs was noted in uninvolved kidney tissue. CONCLUSIONS The loss of α-secretase activity observed here in conjunction with previous findings argue against tumorigenic effects of ADAM9, 10, and 17 supporting that increased nuclear and cytoplasmic expression may be an attempt to compensate for loss of function.
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Affiliation(s)
- Nuray Erin
- Department of Medical Pharmacology, School of Medicine, Akdeniz University, Antalya, Turkey.
| | - Tümay İpekçi
- Department of Urology, Başkent University, Alanya, Turkey
| | - Bahar Akkaya
- Department of Urology, School of Medicine, Akdeniz University, Antalya, Turkey
| | - İrem Hicran Özbudak
- Department of Urology, School of Medicine, Akdeniz University, Antalya, Turkey; Department of Urology, Başkent University, Alanya, Turkey
| | - Mehmet Baykara
- Department of Pathology, School of Medicine, Akdeniz University, Antalya, Turkey
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Feng J, Huang C, Wren JD, Wang DW, Yan J, Zhang J, Sun Y, Han X, Zhang XA. Tetraspanin CD82: a suppressor of solid tumors and a modulator of membrane heterogeneity. Cancer Metastasis Rev 2016; 34:619-33. [PMID: 26335499 DOI: 10.1007/s10555-015-9585-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Tetraspanin CD82 suppresses the progression and metastasis of a wide range of solid malignant tumors. However, its roles in tumorigenesis and hematopoietic malignancy remain unclear. Ubiquitously expressed CD82 restrains cell migration and cell invasion by modulating both cell-matrix and cell-cell adhesiveness and confining outside-in pro-motility signaling. This restraint at least contributes to, if not determines, the metastasis-suppressive activity and, also likely, the physiological functions of CD82. As a modulator of cell membrane heterogeneity, CD82 alters microdomains, trafficking, and topography of the membrane by changing the membrane molecular landscape. The functional activities of membrane molecules and the cytoskeletal interaction of the cell membrane are subsequently altered, followed by changes in cellular functions. Given its pathological and physiological importance, CD82 is a promising candidate for clinically predicting and blocking tumor progression and metastasis and also an emerging model protein for mechanistically understanding cell membrane organization and heterogeneity.
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Affiliation(s)
- Jin Feng
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Chao Huang
- Stephenson Cancer Center and Department of Physiology, University of Oklahoma Health Sciences Center, BRC 1474, 975 NE 10th Street, Oklahoma City, OK, 73104, USA
| | - Jonathan D Wren
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Dao-Wen Wang
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Jizhou Yan
- Institute for Marine Biosystem and Neurosciences, Shanghai Ocean University, Shanghai, China
| | - Jiexin Zhang
- Department of Biochemistry, Nanjing Medical University, Nanjing, China
| | - Yujie Sun
- Department of Biochemistry, Nanjing Medical University, Nanjing, China
| | - Xiao Han
- Department of Biochemistry, Nanjing Medical University, Nanjing, China
| | - Xin A Zhang
- Stephenson Cancer Center and Department of Physiology, University of Oklahoma Health Sciences Center, BRC 1474, 975 NE 10th Street, Oklahoma City, OK, 73104, USA.
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Schmidt F, Müller M, Prox J, Arnold P, Schönherr C, Tredup C, Minder P, Ebsen H, Janssen O, Annaert W, Pietrzik C, Schmidt-Arras D, Sterchi EE, Becker-Pauly C. Tetraspanin 8 is an interactor of the metalloprotease meprin β within tetraspanin-enriched microdomains. Biol Chem 2016; 397:857-69. [DOI: 10.1515/hsz-2016-0126] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 05/04/2016] [Indexed: 11/15/2022]
Abstract
Abstract
Meprin β is a dimeric type I transmembrane protein and acts as an ectodomain sheddase at the cell surface. It has been shown that meprin β cleaves the amyloid precursor protein (APP), thereby releasing neurotoxic amyloid β peptides and implicating a role of meprin β in Alzheimer’s disease. In order to identify non-proteolytic regulators of meprin β, we performed a split ubiquitin yeast two-hybrid screen using a small intestinal cDNA library. In this screen we identified tetraspanin 8 (TSPAN8) as interaction partner for meprin β. As several members of the tetraspanin family were described to interact with metalloproteases thereby affecting their localization and/or activity, we hypothesized similar functions of TSPAN8 in the regulation of meprin β. We employed cell biological methods to confirm direct binding of TSPAN8 to meprin β. Surprisingly, we did not observe an effect of TSPAN8 on the catalytic activity of meprin β nor on the specific cleavage of its substrate APP. However, both proteins were identified as present in tetraspanin-enriched microdomains. Therefore we hypothesize that TSPAN8 might be important for the orchestration of meprin β at the cell surface with impact on certain proteolytic processes that have to be further identified.
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Alzheimer disease: modeling an Aβ-centered biological network. Mol Psychiatry 2016; 21:861-71. [PMID: 27021818 DOI: 10.1038/mp.2016.38] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 02/16/2016] [Accepted: 02/18/2016] [Indexed: 01/15/2023]
Abstract
In genetically complex diseases, the search for missing heritability is focusing on rare variants with large effect. Thanks to next generation sequencing technologies, genome-wide characterization of these variants is now feasible in every individual. However, a lesson from current studies is that collapsing rare variants at the gene level is often insufficient to obtain a statistically significant signal in case-control studies, and that network-based analyses are an attractive complement to classical approaches. In Alzheimer disease (AD), according to the prevalent amyloid cascade hypothesis, the pathology is driven by the amyloid beta (Aβ) peptide. In past years, based on experimental studies, several hundreds of proteins have been shown to interfere with Aβ production, clearance, aggregation or toxicity. Thanks to a manual curation of the literature, we identified 335 genes/proteins involved in this biological network and classified them according to their cellular function. The complete list of genes, or its subcomponents, will be of interest in ongoing AD genetic studies.
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Matthews AL, Noy PJ, Reyat JS, Tomlinson MG. Regulation of A disintegrin and metalloproteinase (ADAM) family sheddases ADAM10 and ADAM17: The emerging role of tetraspanins and rhomboids. Platelets 2016; 28:333-341. [PMID: 27256961 PMCID: PMC5490636 DOI: 10.1080/09537104.2016.1184751] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are ubiquitous transmembrane “molecular scissors” which proteolytically cleave, or shed, the extracellular regions of other transmembrane proteins. ADAM10 is essential for development because it cleaves Notch proteins to induce Notch signaling and regulate cell fate decisions. ADAM17 is regarded as a first line of defense against injury and infection, by releasing tumor necrosis factor α (TNFα) to promote inflammation and epidermal growth factor (EGF) receptor ligands to maintain epidermal barrier function. However, the regulation of ADAM10 and ADAM17 trafficking and activation are not fully understood. This review will describe how the TspanC8 subgroup of tetraspanins (Tspan5, 10, 14, 15, 17, and 33) and the iRhom subgroup of protease-inactive rhomboids (iRhom1 and 2) have emerged as important regulators of ADAM10 and ADAM17, respectively. In particular, they are required for the enzymatic maturation and trafficking to the cell surface of the ADAMs, and there is evidence that different TspanC8s and iRhoms target the ADAMs to distinct substrates. The TspanC8s and iRhoms have not been studied functionally on platelets. On these cells, ADAM10 is the principal sheddase for the platelet collagen receptor GPVI, and the regulatory TspanC8s are Tspan14, 15, and 33, as determined from proteomic data. Platelet ADAM17 is the sheddase for the von Willebrand factor (vWF) receptor GPIb, and iRhom2 is the only iRhom that is expressed. Induced shedding of either GPVI or GPIb has therapeutic potential, since inhibition of either receptor is regarded as a promising anti-thrombotic therapy. Targeting of Tspan14, 15, or 33 to activate platelet ADAM10, or iRhom2 to activate ADAM17, may enable such an approach to be realized, without the toxic side effects of activating the ADAMs on every cell in the body.
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Affiliation(s)
- Alexandra L Matthews
- a School of Biosciences, College of Life and Environmental Sciences, University of Birmingham , Birmingham , UK
| | - Peter J Noy
- a School of Biosciences, College of Life and Environmental Sciences, University of Birmingham , Birmingham , UK
| | - Jasmeet S Reyat
- a School of Biosciences, College of Life and Environmental Sciences, University of Birmingham , Birmingham , UK
| | - Michael G Tomlinson
- a School of Biosciences, College of Life and Environmental Sciences, University of Birmingham , Birmingham , UK
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Yang YG, Sari IN, Zia MF, Lee SR, Song SJ, Kwon HY. Tetraspanins: Spanning from solid tumors to hematologic malignancies. Exp Hematol 2016; 44:322-8. [DOI: 10.1016/j.exphem.2016.02.006] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Revised: 02/11/2016] [Accepted: 02/13/2016] [Indexed: 02/06/2023]
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Vincent B. Regulation of the α-secretase ADAM10 at transcriptional, translational and post-translational levels. Brain Res Bull 2016; 126:154-169. [PMID: 27060611 DOI: 10.1016/j.brainresbull.2016.03.020] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 03/25/2016] [Accepted: 03/30/2016] [Indexed: 12/19/2022]
Abstract
A tremendous gain of interest in the biology of ADAM10 emerged during the past 15 years when it has first been shown that this protease was able to target the α-site of the β-amyloid precursor protein (βAPP) and later confirmed as the main physiological α-secretase activity. However, beside its well-established implication in the so-called non-amyloidogenic processing of βAPP and its probable protective role against Alzheimer's disease (AD), this metalloprotease also cleaves many other substrates, thereby being implicated in various physiological as well as pathological processes such as cancer and inflammation. Thus, in view of possible effective therapeutic interventions, a full comprehension of how ADAM10 is up and down regulated is required. This review discusses our current knowledge concerning the implication of this enzyme in AD as well as its more recently established roles in other brain disorders and provides a detailed up-date on its various transcriptional, translational and post-translational modulations.
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Affiliation(s)
- Bruno Vincent
- Mahidol University, Institute of Molecular Biosciences, Nakhon Pathom 73170, Thailand; Centre National de la Recherche Scientifique, 2 rue Michel Ange, 75016 Paris, France.
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Facey A, Pinar I, Arthur JF, Qiao J, Jing J, Mado B, Carberry J, Andrews RK, Gardiner EE. A-Disintegrin-And-Metalloproteinase (ADAM) 10 Activity on Resting and Activated Platelets. Biochemistry 2016; 55:1187-94. [DOI: 10.1021/acs.biochem.5b01102] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Adam Facey
- Australian
Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia 3004
| | - Isaac Pinar
- Department
of Mechanical and Aerospace Engineering, Monash University, Clayton, Victoria, Australia 3168
| | - Jane F. Arthur
- Australian
Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia 3004
| | - Jianlin Qiao
- Australian
Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia 3004
| | - Jing Jing
- Australian
Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia 3004
| | - Belden Mado
- Australian
Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia 3004
| | - Josie Carberry
- Department
of Mechanical and Aerospace Engineering, Monash University, Clayton, Victoria, Australia 3168
| | - Robert K. Andrews
- Australian
Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia 3004
| | - Elizabeth E. Gardiner
- Australian
Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia 3004
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Chen AC, Kim S, Shepardson N, Patel S, Hong S, Selkoe DJ. Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis. J Cell Biol 2015; 211:1157-76. [PMID: 26694839 PMCID: PMC4687875 DOI: 10.1083/jcb.201502001] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 11/11/2015] [Indexed: 12/20/2022] Open
Abstract
Many single-transmembrane proteins are sequentially cleaved by ectodomain-shedding α-secretases and the γ-secretase complex, a process called regulated intramembrane proteolysis (RIP). These cleavages are thought to be spatially and temporally separate. In contrast, we provide evidence for a hitherto unrecognized multiprotease complex containing both α- and γ-secretase. ADAM10 (A10), the principal neuronal α-secretase, interacted and cofractionated with γ-secretase endogenously in cells and mouse brain. A10 immunoprecipitation yielded γ-secretase proteolytic activity and vice versa. In agreement, superresolution microscopy showed that portions of A10 and γ-secretase colocalize. Moreover, multiple γ-secretase inhibitors significantly increased α-secretase processing (r = -0.86) and decreased β-secretase processing of β-amyloid precursor protein. Select members of the tetraspanin web were important both in the association between A10 and γ-secretase and the γ → α feedback mechanism. Portions of endogenous BACE1 coimmunoprecipitated with γ-secretase but not A10, suggesting that β- and α-secretases can form distinct complexes with γ-secretase. Thus, cells possess large multiprotease complexes capable of sequentially and efficiently processing transmembrane substrates through a spatially coordinated RIP mechanism.
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Affiliation(s)
- Allen C Chen
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
| | - Sumin Kim
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
| | - Nina Shepardson
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
| | - Sarvagna Patel
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
| | - Soyon Hong
- Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115
| | - Dennis J Selkoe
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
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The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain. Prog Neurobiol 2015; 135:1-20. [PMID: 26522965 DOI: 10.1016/j.pneurobio.2015.10.003] [Citation(s) in RCA: 169] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 09/23/2015] [Accepted: 10/26/2015] [Indexed: 01/07/2023]
Abstract
Proteins belonging to the 'A Disintegrin And Metalloproteinase' (ADAM) family are membrane-anchored proteases that are able to cleave the extracellular domains of several membrane-bound proteins in a process known as 'ectodomain shedding'. In the central nervous system, ADAM10 has attracted the most attention, since it was described as the amyloid precursor protein α-secretase over ten years ago. Despite the excitement over the potential of ADAM10 as a novel drug target in Alzheimer disease, the physiological functions of ADAM10 in the brain are not yet well understood. This is largely because of the embryonic lethality of ADAM10-deficient mice, which results from the loss of cleavage and signaling of the Notch receptor, another ADAM10 substrate. However, the recent generation of conditional ADAM10-deficient mice and the identification of further ADAM10 substrates in the brain has revealed surprisingly numerous and fundamental functions of ADAM10 in the development of the embryonic brain and also in the homeostasis of adult neuronal networks. Mechanistically, ADAM10 controls these functions by utilizing unique postsynaptic substrates in the central nervous system, in particular synaptic cell adhesion molecules, such as neuroligin-1, N-cadherin, NCAM, Ephrin A2 and A5. Consequently, a dysregulation of ADAM10 activity is linked to psychiatric and neurological diseases, such as epilepsy, fragile X syndrome and Huntington disease. This review highlights the recent progress in understanding the substrates and function as well as the regulation and cell biology of ADAM10 in the central nervous system and discusses the value of ADAM10 as a drug target in brain diseases.
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Conant K, Allen M, Lim ST. Activity dependent CAM cleavage and neurotransmission. Front Cell Neurosci 2015; 9:305. [PMID: 26321910 PMCID: PMC4531370 DOI: 10.3389/fncel.2015.00305] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 07/27/2015] [Indexed: 12/13/2022] Open
Abstract
Spatially localized proteolysis represents an elegant means by which neuronal activity dependent changes in synaptic structure, and thus experience dependent learning and memory, can be achieved. In vitro and in vivo studies suggest that matrix metalloproteinase and adamalysin activity is concentrated at the cell surface, and emerging evidence suggests that increased peri-synaptic expression, release and/or activation of these proteinases occurs with enhanced excitatory neurotransmission. Synaptically expressed cell adhesion molecules (CAMs) could therefore represent important targets for neuronal activity-dependent proteolysis. Several CAM subtypes are expressed at the synapse, and their cleavage can influence the efficacy of synaptic transmission through a variety of non-mutually exclusive mechanisms. In the following review, we discuss mechanisms that regulate neuronal activity-dependent synaptic CAM shedding, including those that may be calcium dependent. We also highlight CAM targets of activity-dependent proteolysis including neuroligin and intercellular adhesion molecule-5 (ICAM-5). We include discussion focused on potential consequences of synaptic CAM shedding, with an emphasis on interactions between soluble CAM cleavage products and specific pre- and post-synaptic receptors.
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Affiliation(s)
- Katherine Conant
- Department of Neuroscience and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center Washington, DC, USA
| | - Megan Allen
- Department of Neuroscience and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center Washington, DC, USA
| | - Seung T Lim
- Department of Neuroscience and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center Washington, DC, USA
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Skaar K, Korza HJ, Tarry M, Sekyrova P, Högbom M. Expression and Subcellular Distribution of GFP-Tagged Human Tetraspanin Proteins in Saccharomyces cerevisiae. PLoS One 2015. [PMID: 26218426 PMCID: PMC4517926 DOI: 10.1371/journal.pone.0134041] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Tetraspanins are integral membrane proteins that function as organizers of multimolecular complexes and modulate function of associated proteins. Mammalian genomes encode approximately 30 different members of this family and remotely related eukaryotic species also contain conserved tetraspanin homologs. Tetraspanins are involved in a number of fundamental processes such as regulation of cell migration, fusion, immunity and signaling. Moreover, they are implied in numerous pathological states including mental disorders, infectious diseases or cancer. Despite the great interest in tetraspanins, the structural and biochemical basis of their activity is still largely unknown. A major bottleneck lies in the difficulty of obtaining stable and homogeneous protein samples in large quantities. Here we report expression screening of 15 members of the human tetraspanin superfamily and successful protocols for the production in S. cerevisiae of a subset of tetraspanins involved in human cancer development. We have demonstrated the subcellular localization of overexpressed tetraspanin-green fluorescent protein fusion proteins in S. cerevisiae and found that despite being mislocalized, the fusion proteins are not degraded. The recombinantly produced tetraspanins are dispersed within the endoplasmic reticulum membranes or localized in granule-like structures in yeast cells. The recombinantly produced tetraspanins can be extracted from the membrane fraction and purified with detergents or the poly (styrene-co-maleic acid) polymer technique for use in further biochemical or biophysical studies.
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Affiliation(s)
- Karin Skaar
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Henryk J. Korza
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Michael Tarry
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Petra Sekyrova
- Department of Pharmacology and Physiology, Karolinska Institutet, Stockholm, Sweden
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Martin Högbom
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
- * E-mail:
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Detchokul S, Williams ED, Parker MW, Frauman AG. Tetraspanins as regulators of the tumour microenvironment: implications for metastasis and therapeutic strategies. Br J Pharmacol 2015; 171:5462-90. [PMID: 23731188 DOI: 10.1111/bph.12260] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Revised: 05/16/2013] [Accepted: 05/16/2013] [Indexed: 12/13/2022] Open
Abstract
UNLABELLED One of the hallmarks of cancer is the ability to activate invasion and metastasis. Cancer morbidity and mortality are largely related to the spread of the primary, localized tumour to adjacent and distant sites. Appropriate management and treatment decisions based on predicting metastatic disease at the time of diagnosis is thus crucial, which supports better understanding of the metastatic process. There are components of metastasis that are common to all primary tumours: dissociation from the primary tumour mass, reorganization/remodelling of extracellular matrix, cell migration, recognition and movement through endothelial cells and the vascular circulation and lodgement and proliferation within ectopic stroma. One of the key and initial events is the increased ability of cancer cells to move, escaping the regulation of normal physiological control. The cellular cytoskeleton plays an important role in cancer cell motility and active cytoskeletal rearrangement can result in metastatic disease. This active change in cytoskeletal dynamics results in manipulation of plasma membrane and cellular balance between cellular adhesion and motility which in turn determines cancer cell movement. Members of the tetraspanin family of proteins play important roles in regulation of cancer cell migration and cancer-endothelial cell interactions, which are critical for cancer invasion and metastasis. Their involvements in active cytoskeletal dynamics, cancer metastasis and potential clinical application will be discussed in this review. In particular, the tetraspanin member, CD151, is highlighted for its major role in cancer invasion and metastasis. LINKED ARTICLES This article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24.
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Affiliation(s)
- S Detchokul
- Clinical Pharmacology and Therapeutics Unit, Department of Medicine (Austin Health/Northern Health), The University of Melbourne, Heidelberg, Vic., Australia
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48
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Yin Y, Deng X, Liu Z, Baldwin LA, Lefringhouse J, Zhang J, Hoff JT, Erfani SF, Rucker EB, O'Connor K, Liu C, Wu Y, Zhou BP, Yang XH. CD151 represses mammary gland development by maintaining the niches of progenitor cells. Cell Cycle 2015; 13:2707-22. [PMID: 25486358 DOI: 10.4161/15384101.2015.945823] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Tetraspanin CD151 interacts with laminin-binding integrins (i.e., α3β1, α6β1 and α6β4) and other cell surface molecules to control diverse cellular and physiological processes, ranging from cell adhesion, migration and survival to tissue architecture and homeostasis. Here, we report a novel role of CD151 in maintaining the branching morphogenesis and activity of progenitor cells during the pubertal development of mammary glands. In contrast to the disruption of laminin-binding integrins, CD151 removal in mice enhanced the tertiary branching in mammary glands by 2.4-fold and the number of terminal end buds (TEBs) by 30%, while having minimal influence on either primary or secondary ductal branching. Consistent with these morphological changes are the skewed distribution of basal/myoepithelial cells and a 3.2-fold increase in proliferating Ki67-positive cells. These novel observations suggest that CD151 impacts the branching morphogenesis of mammary glands by upregulating the activities of bipotent progenitor cells. Indeed, our subsequent analyses indicate that upon CD151 removal the proportion of CD24(Hi)CD49f(Low) progenitor cells in the mammary gland increased by 34%, and their proliferating and differentiating activities were significantly upregulated. Importantly, fibronectin, a pro-branching extracellular matrix (ECM) protein deposited underlying mammary epithelial or progenitor cells, increased by >7.2-fold. Moreover, there was a concomitant increase in the expression and nuclear distribution of Slug, a transcription factor implicated in the maintenance of mammary progenitor cell activities. Taken together, our studies demonstrate that integrin-associated CD151 represses mammary branching morphogenesis by controlling progenitor cell activities, ECM integrity and transcription program.
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Affiliation(s)
- Yuanqin Yin
- a Cancer Institute; First Affiliated Hospital ; China Medical University ; Shenyang , China
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Millan MJ. The epigenetic dimension of Alzheimer's disease: causal, consequence, or curiosity? DIALOGUES IN CLINICAL NEUROSCIENCE 2015. [PMID: 25364287 PMCID: PMC4214179 DOI: 10.31887/dcns.2014.16.3/mmillan] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Early-onset, familial Alzheimer's disease (AD) is rare and may be attributed to disease-causinq mutations. By contrast, late onset, sporadic (non-Mendelian) AD is far more prevalent and reflects the interaction of multiple genetic and environmental risk factors, together with the disruption of epigenetic mechanisms controlling gene expression. Accordingly, abnormal patterns of histone acetylation and methylation, as well as anomalies in global and promoter-specific DNA methylation, have been documented in AD patients, together with a deregulation of noncoding RNA. In transgenic mouse models for AD, epigenetic dysfunction is likewise apparent in cerebral tissue, and it has been directly linked to cognitive and behavioral deficits in functional studies. Importantly, epigenetic deregulation interfaces with core pathophysiological processes underlying AD: excess production of Aβ42, aberrant post-translational modification of tau, deficient neurotoxic protein clearance, axonal-synaptic dysfunction, mitochondrial-dependent apoptosis, and cell cycle re-entry. Reciprocally, DNA methylation, histone marks and the levels of diverse species of microRNA are modulated by Aβ42, oxidative stress and neuroinflammation. In conclusion, epigenetic mechanisms are broadly deregulated in AD mainly upstream, but also downstream, of key pathophysiological processes. While some epigenetic shifts oppose the evolution of AD, most appear to drive its progression. Epigenetic changes are of irrefutable importance for AD, but they await further elucidation from the perspectives of pathogenesis, biomarkers and potential treatment.
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Affiliation(s)
- Mark J Millan
- Pole of Innovation in Neuropsychiatry, Institut de Recherche Servier, Croissy-sur-Seine, France
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50
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Ebsen H, Lettau M, Kabelitz D, Janssen O. Subcellular localization and activation of ADAM proteases in the context of FasL shedding in T lymphocytes. Mol Immunol 2015; 65:416-28. [PMID: 25745808 DOI: 10.1016/j.molimm.2015.02.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 01/20/2015] [Accepted: 02/08/2015] [Indexed: 10/23/2022]
Abstract
The "A Disintegrin And Metalloproteinases" (ADAMs) form a subgroup of the metzincin endopeptidases. Proteolytically active members of this protein family act as sheddases and govern key processes in development and inflammation by regulating cell surface expression and release of cytokines, growth factors, adhesion molecules and their receptors. In T lymphocytes, ADAM10 sheds the death factor Fas Ligand (FasL) and thereby regulates T cell activation, death and effector function. Although FasL shedding by ADAM10 was confirmed in several studies, its regulation is still poorly defined. We recently reported that ADAM10 is highly abundant on T cells whereas its close relative ADAM17 is expressed at low levels and transiently appears at the cell surface upon stimulation. Since FasL is also stored intracellularly and brought to the plasma membrane upon stimulation, we addressed where the death factor gets exposed to ADAM proteases. We report for the first time that both ADAM10 and ADAM17 are associated with FasL-containing secretory lysosomes. Moreover, we demonstrate that TCR/CD3/CD28-stimulation induces a partial positioning of both proteases and FasL to lipid rafts and only the activation-induced raft-positioning results in FasL processing. TCR/CD3/CD28-induced FasL proteolysis is markedly affected by reducing both ADAM10 and ADAM17 protein levels, indicating that in human T cells also ADAM17 is implicated in FasL processing. Since FasL shedding is affected by cholesterol depletion and by inhibition of Src kinases or palmitoylation, we conclude that it requires mobilization and co-positioning of ADAM proteases in lipid raft-like platforms associated with an activation of raft-associated Src-family kinases.
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Affiliation(s)
- Henriette Ebsen
- University of Kiel, Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3 Bldg 17, D-24105 Kiel, Germany
| | - Marcus Lettau
- University of Kiel, Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3 Bldg 17, D-24105 Kiel, Germany
| | - Dieter Kabelitz
- University of Kiel, Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3 Bldg 17, D-24105 Kiel, Germany
| | - Ottmar Janssen
- University of Kiel, Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3 Bldg 17, D-24105 Kiel, Germany.
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