Tetraspanin

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Martin E. Hemler - One of the best experts on this subject based on the ideXlab platform.

  • Tetraspanin proteins regulate membrane type 1 matrix metalloproteinase dependent pericellular proteolysis
    Molecular Biology of the Cell, 2009
    Co-Authors: Marc A Lafleur, Daosong Xu, Martin E. Hemler
    Abstract:

    Membrane type-1 matrix metalloproteinase (MT1-MMP) supports tumor cell invasion through extracellular matrix barriers containing fibrin, collagen, fibronectin, and other proteins. Here, we show that simultaneous knockdown of two or three members of the Tetraspanin family (CD9, CD81, and TSPAN12) markedly decreases MT1-MMP proteolytic functions in cancer cells. Affected functions include fibronectin proteolysis, invasion and growth in three-dimensional fibrin and collagen gels, and MMP-2 activation. Tetraspanin proteins (CD9, CD81, and TSPAN2) selectively coimmunoprecipitate and colocalize with MT1-MMP. Although Tetraspanins do not affect the initial biosynthesis of MT1-MMP, they do protect the newly synthesized protein from lysosomal degradation and support its delivery to the cell surface. Interfering with MT1-MMP-Tetraspanin collaboration may be a useful therapeutic approach to limit cancer cell invasion and metastasis.

  • Targeting of Tetraspanin proteins — potential benefits and strategies
    Nature Reviews Drug Discovery, 2008
    Co-Authors: Martin E. Hemler
    Abstract:

    Tetraspanins are a family of transmembrane proteins with emerging roles in both normal and pathological processes including development, fertilization, malignancy, immune-cell function and infectious disease. Here, Hemler reviews the functions of specific Tetraspanins with the potential to be therapeutically targeted, and proposes possible strategies that may be pursued. The Tetraspanin transmembrane proteins have emerged as key players in malignancy, the immune system, during fertilization and infectious disease processes. Tetraspanins engage in a wide range of specific molecular interactions, occurring through the formation of Tetraspanin-enriched microdomains (TEMs). TEMs therefore serve as a starting point for understanding how Tetraspanins affect cell signalling, adhesion, morphology, motility, fusion and virus infection. An abundance of recent evidence suggests that targeting Tetraspanins, for example, by monoclonal antibodies, soluble large-loop proteins or RNAi technology, should be therapeutically beneficial. There are 33 mammalian Tetraspanin proteins, each with characteristic structural features, including a conserved CCG motif in the large extracellular loop. Genetic evidence in fungi, worms, flies, mice and humans establishes that Tetraspanins have key roles in many processes including development, fertilization, invasion and immune-cell function. Tetraspanins, which are expressed on nearly all cell and tissue types, also modulate cell morphology, motility, invasion, fusion, adhesion strengthening, signalling and protein trafficking. Tetraspanins organize laterally, into Tetraspanin-enriched microdomains (TEMs). At the core of TEMs are Tetraspanins engaging in direct protein–protein interactions with themselves and other proteins, including the immunoglobulin superfamily members EWI-2 and EWI-F, Claudin-1, epidermal growth factor receptor (EGFR) membrane-bound ligands, integrins and Syntenin-1. These primary complexes are then joined into a network of looser secondary interactions involving many additional proteins. Tetraspanins and many of their partner proteins (for example, integrins, EWI proteins and Claudin-1) undergo protein palmitoylation, which helps to stabilize secondary interactions within TEMs. Tetraspanins contribute to a number of normal and pathological processes that could be targeted therapeutically. For example, CD151 may support primary tumour growth as well as metastasis and angiogenesis, whereas Tetraspanins CD9 and CD81 are required for oocyte fertilization. In addition, several Tetraspanins contribute to the functions of platelets and lymphocytes, thereby enhancing blood clotting and affecting numerous immune functions. Tetraspanins make substantial contributions towards infectious-disease pathologies. For HIV-1, human T-cell lymphotropic virus type 1 and other viruses, Tetraspanins affect virus-induced cell fusion events and/or virus assembly and release. In hepatocytes, Tetraspanin CD81 is needed for the initial steps in hepatitis C virus binding and infection, and for invasion by sporozoites from malaria-causing parasites. Promising in vivo results suggest that targeting of Tetraspanins may be therapeutically useful for injury repair, for cancer models and for combating infectious diseases. Anti-Tetraspanin monoclonal antibodies, Tetraspanin-derived recombinant soluble extracellular loops and RNAi knockdown strategies have all shown potential for effective modulation of Tetraspanin functions.

  • targeting of Tetraspanin proteins potential benefits and strategies
    Nature Reviews Drug Discovery, 2008
    Co-Authors: Martin E. Hemler
    Abstract:

    The Tetraspanin transmembrane proteins have emerged as key players in malignancy, the immune system, during fertilization and infectious disease processes. Tetraspanins engage in a wide range of specific molecular interactions, occurring through the formation of Tetraspanin-enriched microdomains (TEMs). TEMs therefore serve as a starting point for understanding how Tetraspanins affect cell signalling, adhesion, morphology, motility, fusion and virus infection. An abundance of recent evidence suggests that targeting Tetraspanins, for example, by monoclonal antibodies, soluble large-loop proteins or RNAi technology, should be therapeutically beneficial.

  • a novel cysteine cross linking method reveals a direct association between claudin 1 and Tetraspanin cd9
    Molecular & Cellular Proteomics, 2007
    Co-Authors: Oleg V Kovalenko, Xiuwei H Yang, Martin E. Hemler
    Abstract:

    Tetraspanins serve as molecular organizers of multiprotein microdomains in cell membranes. Hence to understand functions of Tetraspanin proteins, it is critical to identify laterally interacting partner proteins. Here we used a novel technical approach involving exposure and cross-linking of membrane-proximal cysteines coupled with LC-MS/MS protein identification. In this manner we identified nine potential Tetraspanin CD9 partners, including claudin-1. Chemical cross-linking yielded a CD9-claudin-1 heterodimer, thus confirming direct association and adding claudin-1 to the short list of proteins that can directly associate with CD9. Interaction of CD9 (and other Tetraspanins) with claudin-1 was supported by subcellular colocalization and was confirmed in multiple cell lines, although other claudins (claudin-2, -3, -4, -5, and -7) associated to a much lesser extent. Moreover claudin-1 was distributed very similarly to CD9 in sucrose gradients and, like CD9, was released from A431 and A549 cells upon cholesterol depletion. These biochemical features of claudin-1 are characteristic of Tetraspanin microdomain proteins. Although claudins are major structural components of intercellular tight junctions, CD9-claudin-1 complexes did not reside in tight junctions, and depletion of key Tetraspanins (CD9 and CD151) by small interfering RNA had no effect on paracellular permeability. However, Tetraspanin depletion did cause a marked decrease in the stability of newly synthesized claudin-1. In conclusion, these results (a) validate a technical approach that appears to be particularly well suited for identifying protein partners directly associated with Tetraspanins or with other proteins that contain membrane-proximal cysteines and (b) provide insight into how non-junctional claudins may be regulated in the context of Tetraspanin-enriched microdomains. Molecular & Cellular Proteomics 6: 1855–1867, 2007.

  • Tetraspanin functions and associated microdomains
    Nature Reviews Molecular Cell Biology, 2005
    Co-Authors: Martin E. Hemler
    Abstract:

    Cell-surface proteins of the Tetraspanin family are small, and often hidden by a canopy of tall glycoprotein neighbours in the cell membrane. Consequently, Tetraspanins have been understudied and underappreciated, despite their presence on nearly all cell and tissue types. Important new genetic evidence has now emerged, and is bolstered by new insights into the cell biology, signalling and biochemistry of Tetraspanins. These new findings provide a framework for better understanding of these mysterious molecules in the regulation of cellular processes, from signalling to motility. Tetraspanins do not protrude far above the plasma membrane, and do not typically bind external ligands. Nonetheless, this large family of molecules (for example, there are 32 in mammals) has considerable functional importance. By organizing multimolecular membrane complexes, Tetraspanins regulate cell migration, fusion and signalling events. Mammalian genetics has yielded new insights into Tetraspanin functions. For example, CD151 contributes to normal kidney, skin and platelet function; peripherin/RDS and ROM-1 support retinal integrity; and TALLA-1/A15 is important for brain function. Other Tetraspanins enable sperm–egg fusion (CD9), support nervous system development (CD9, CD81), regulate monocyte fusion (CD9, CD81) and contribute to T-cell proliferation (CD151, CD37, Tssc6, CD81). Additional definitive insights come from genetic analyses in other species. Drosophila melanogaster Tetraspanins are linked to light-induced retinal degeneration and haemocyte proliferation. The first reported Caenorhabditis elegans Tetraspanin mutation leads to a disrupted epidermis, and several fungal Tetraspanins are linked to host leaf penetration. These results from non-mammalian species provide important clues regarding the functions of Tetraspanins in mammals. Although the Tetraspanins CD81 and CD151 do not affect integrin-dependent ligand binding and cell adhesion, they do markedly influence integrin-dependent adhesion strengthening. Such results strongly suggest that Tetraspanins can modulate the cytoskeleton, but specific connections remain to be established. Antibodies to the Tetraspanins CD9 and CD81 can reduce cell proliferation. In both cases, recruitment of phosphatidylinositol 4-kinase, activation of Shc, and activation of the extracellular signal-regulated kinase (ERK)–mitogen-activated protein kinase (MAPK) pathway might underlie effects on proliferation. These same pathways might also link CD9 to apoptosis. CD151 and CD82 have also been linked to various signalling events, which could help to explain their effects on cell morphology, motility and tumour progression. Understanding the organization of Tetraspanin-enriched microdomains (TEMs) is essential for understanding Tetraspanin functions. At the core of TEMs are various direct protein–protein partnerships, both homophilic and heterophilic. These primary building blocks are then assembled into a larger network of secondary interactions, with protein palmitoylation having an important supporting role. TEMs are distinct from lipid rafts in terms of the identity of components, and sensitivity to temperature, cholesterol, detergents and protein palmitoylation.

Eric Rubinstein - One of the best experts on this subject based on the ideXlab platform.

  • Regulation of the trafficking and the function of the metalloprotease ADAM10 by Tetraspanins.
    Biochemical Society Transactions, 2017
    Co-Authors: Julien Saint-pol, Stéphanie Charrin, Claude Boucheix, Etienne Eschenbrenner, Emmanuel Dornier, Eric Rubinstein
    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 Alzheimer9s disease.

  • The Major CD9 and CD81 Molecular Partner
    Journal of Biological Chemistry, 2017
    Co-Authors: Stéphanie Charrin, Franois Le Naour, Michael Oualid, Martine Billard, Gilbert Faure, Claude Boucheix, Samir M. Hanash, Eric Rubinstein
    Abstract:

    By associating with specific partner molecules and with each other, the Tetraspanins are thought to assem- ble multimolecular complexes that may be especially relevant with respect to metastasis. We have previously identified a 135-kDa molecule (CD9P-1) as a major mo- lecular partner of CD9 in cancer cell lines. This molecule was identified, after immunoaffinity purification and mass spectrometry analysis, as the protein encoded by the KIAA1436 gene and the human ortholog of a rat protein known as FPRP. Cross-linking experiments de- tected a complex of the size of CD9 plus CD9P-1, showing that these glycoproteins directly associate with each other, probably in the absence of any other molecule. The use of chimeric CD9/CD82 molecules revealed the role of the second half of CD9, comprising the large extracellular loop and the fourth transmembrane do- main. CD9P-1 was also shown to form separate com- plexes with CD81 and with an unidentified 175-kDa mol- ecule. It also associated with other Tetraspanins under conditions maintaining Tetraspanin/Tetraspanin inter- actions. The identification of a protein strongly linked to the Tetraspanin web and the production of a specific monoclonal antibody will help to further characterize the role of this “web” under physiological and patholog- ical conditions.

  • Tetraspanins at a glance
    Journal of Cell Science, 2014
    Co-Authors: Stéphanie Charrin, Claude Boucheix, Stéphanie Jouannet, Eric Rubinstein
    Abstract:

    Tetraspanins are a family of proteins with four transmembrane domains that play a role in many aspects of cell biology and physiology; they are also used by several pathogens for infection and regulate cancer progression. Many Tetraspanins associate specifically and directly with a limited number of proteins, and also with other Tetraspanins, thereby generating a hierarchical network of interactions. Through these interactions, Tetraspanins are believed to have a role in cell and membrane compartmentalization. In this Cell Science at a Glance article and the accompanying poster, we describe the basic principles underlying Tetraspanin-based assemblies and highlight examples of how Tetraspanins regulate the trafficking and function of their partner proteins that are required for the normal development and function of several organs, including, in humans, the eye, the kidney and the immune system.

  • Viruses and Tetraspanins: lessons from single molecule approaches.
    Viruses, 2014
    Co-Authors: Selma Dahmane, Eric Rubinstein, Pierre-emmanuel Milhiet
    Abstract:

    Tetraspanins are four-span membrane proteins that are widely distributed in multi-cellular organisms and involved in several infectious diseases. They have the unique property to form a network of protein-protein interaction within the plasma membrane, due to the lateral associations with one another and with other membrane proteins. Tracking Tetraspanins at the single molecule level using fluorescence microscopy has revealed the membrane behavior of the Tetraspanins CD9 and CD81 in epithelial cell lines, providing a first dynamic view of this network. Single molecule tracking highlighted that these 2 proteins can freely diffuse within the plasma membrane but can also be trapped, permanently or transiently, in Tetraspanin-enriched areas. More recently, a similar strategy has been used to investigate Tetraspanin membrane behavior in the context of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) infection. In this review we summarize the main results emphasizing the relationship in terms of membrane partitioning between Tetraspanins, some of their partners such as Claudin-1 and EWI-2, and viral proteins during infection. These results will be analyzed in the context of other membrane microdomains, stressing the difference between raft and Tetraspanin-enriched microdomains, but also in comparison with virus diffusion at the cell surface. New advanced single molecule techniques that could help to further explore Tetraspanin assemblies will be also discussed.

  • Organisation of the Tetraspanin Web
    Tetraspanins, 2013
    Co-Authors: Eric Rubinstein, Stéphanie Charrin, Michael G. Tomlinson
    Abstract:

    Tetraspanins are currently hypothesized to promote membrane compartmentalization, through their ability to organize a network of molecular interactions termed the Tetraspanin web or Tetraspanin-enriched microdomains. In this chapter we will describe how the discovery of this unique ability of Tetraspanins to interact with one another and with many other surface proteins led to this concept, and will discuss the hierarchical organization of these structures. We will also show how Tetraspanins modulate the function of the proteins they associate with, including the regulation of trafficking, ligand binding, signal transduction and enzymatic activities.

Christopher S Stipp - One of the best experts on this subject based on the ideXlab platform.

  • The CD9/CD81 Tetraspanin Complex and Tetraspanin CD151 Regulate α3β1 Integrin-Dependent Tumor Cell Behaviors by Overlapping but Distinct Mechanisms
    PLOS ONE, 2013
    Co-Authors: Elisabeth A. Gustafson-wagner, Christopher S Stipp
    Abstract:

    Integrin α3β1 potently promotes cell motility on its ligands, laminin-332 and laminin-511, and this may help to explain why α3β1 has repeatedly been linked to breast carcinoma progression and metastasis. The pro-migratory functions of α3β1 depend strongly on lateral interactions with cell surface Tetraspanin proteins. Tetraspanin CD151 interacts directly with the α3 integrin subunit and links α3β1 integrin to other Tetraspanins, including CD9 and CD81. Loss of CD151 disrupts α3β1 association with other Tetraspanins and impairs α3β1-dependent motility. However, the extent to which Tetraspanins other than CD151 are required for specific α3β1 functions is unclear. To begin to clarify which aspects of α3β1 function require which Tetraspanins, we created breast carcinoma cells depleted of both CD9 and CD81 by RNA interference. Silencing both of these closely related Tetraspanins was required to uncover their contributions to α3β1 function. We then directly compared our CD9/CD81-silenced cells to CD151-silenced cells. Both CD9/CD81-silenced cells and CD151-silenced cells showed delayed α3β1-dependent cell spreading on laminin-332. Surprisingly, however, once fully spread, CD9/CD81-silenced cells, but not CD151-silenced cells, displayed impaired α3β1-dependent directed motility and altered front-rear cell morphology. Also unexpectedly, the CD9/CD81 complex, but not CD151, was required to promote α3β1 association with PKCα in breast carcinoma cells, and a PKC inhibitor mimicked aspects of the CD9/CD81-silenced cell motility defect. Our data reveal overlapping, but surprisingly distinct contributions of specific Tetraspanins to α3β1 integrin function. Importantly, some of CD9/CD81's α3β1 regulatory functions may not require CD9/CD81 to be physically linked to α3β1 by CD151.

  • laminin binding integrins and their Tetraspanin partners as potential antimetastatic targets
    Expert Reviews in Molecular Medicine, 2010
    Co-Authors: Christopher S Stipp
    Abstract:

    : Within the integrin family of cell adhesion receptors, integrins alpha3beta1, alpha6beta1, alpha6beta4 and alpha7beta1 make up a laminin-binding subfamily. The literature is divided on the role of these laminin-binding integrins in metastasis, with different studies indicating either pro- or antimetastatic functions. The opposing roles of the laminin-binding integrins in different settings might derive in part from their unusually robust associations with Tetraspanin proteins. Tetraspanins organise integrins into multiprotein complexes within discrete plasma membrane domains termed Tetraspanin-enriched microdomains (TEMs). TEM association is crucial to the strikingly rapid cell migration mediated by some of the laminin-binding integrins. However, emerging data suggest that laminin-binding integrins also promote the stability of E-cadherin-based cell-cell junctions, and that Tetraspanins are essential for this function as well. Thus, TEM association endows the laminin-binding integrins with both pro-invasive functions (rapid migration) and anti-invasive functions (stable cell junctions), and the composition of TEMs in different cell types might help determine the balance between these opposing activities. Unravelling the Tetraspanin control mechanisms that regulate laminin-binding integrins will help to define the settings where inhibiting the function of these integrins would be helpful rather than harmful, and may create opportunities to modulate integrin activity in more sophisticated ways than simple functional blockade.

  • palmitoylation supports assembly and function of integrin Tetraspanin complexes
    Journal of Cell Biology, 2004
    Co-Authors: Xiuwei Yang, Oleg V Kovalenko, Wei Tang, Christoph Claas, Christopher S Stipp, Martin E. Hemler
    Abstract:

    As observed previously, Tetraspanin palmitoylation promotes Tetraspanin microdomain assembly. Here, we show that palmitoylated integrins (α3, α6, and β4 subunits) and Tetraspanins (CD9, CD81, and CD63) coexist in substantially overlapping complexes. Removal of β4 palmitoylation sites markedly impaired cell spreading and signaling through p130Cas on laminin substrate. Also in palmitoylation-deficient β4, secondary associations with Tetraspanins (CD9, CD81, and CD63) were diminished and cell surface CD9 clustering was decreased, whereas core α6β4–CD151 complex formation was unaltered. There is also a functional connection between CD9 and β4 integrins, as evidenced by anti-CD9 antibody effects on β4-dependent cell spreading. Notably, β4 palmitoylation neither increased localization into “light membrane” fractions of sucrose gradients nor decreased solubility in nonionic detergents—hence it does not promote lipid raft association. Instead, palmitoylation of β4 (and of the closely associated Tetraspanin CD151) promotes CD151–α6β4 incorporation into a network of secondary Tetraspanin interactions (with CD9, CD81, CD63, etc.), which provides a novel framework for functional regulation.

  • Palmitoylation supports assembly and function of integrin–Tetraspanin complexes
    Journal of Cell Biology, 2004
    Co-Authors: Xiuwei Yang, Oleg V Kovalenko, Wei Tang, Christoph Claas, Christopher S Stipp, Martin E. Hemler
    Abstract:

    As observed previously, Tetraspanin palmitoylation promotes Tetraspanin microdomain assembly. Here, we show that palmitoylated integrins (α3, α6, and β4 subunits) and Tetraspanins (CD9, CD81, and CD63) coexist in substantially overlapping complexes. Removal of β4 palmitoylation sites markedly impaired cell spreading and signaling through p130Cas on laminin substrate. Also in palmitoylation-deficient β4, secondary associations with Tetraspanins (CD9, CD81, and CD63) were diminished and cell surface CD9 clustering was decreased, whereas core α6β4–CD151 complex formation was unaltered. There is also a functional connection between CD9 and β4 integrins, as evidenced by anti-CD9 antibody effects on β4-dependent cell spreading. Notably, β4 palmitoylation neither increased localization into “light membrane” fractions of sucrose gradients nor decreased solubility in nonionic detergents—hence it does not promote lipid raft association. Instead, palmitoylation of β4 (and of the closely associated Tetraspanin CD151) promotes CD151–α6β4 incorporation into a network of secondary Tetraspanin interactions (with CD9, CD81, CD63, etc.), which provides a novel framework for functional regulation.

  • dynamic regulation of a gpcr Tetraspanin g protein complex on intact cells central role of cd81 in facilitating gpr56 gαq 11 association
    Molecular Biology of the Cell, 2004
    Co-Authors: Kevin D Little, Martin E. Hemler, Christopher S Stipp
    Abstract:

    By means of a variety of intracellular scaffolding proteins, a vast number of heterotrimeric G protein–coupled receptors (GPCRs) may achieve specificity in signaling through a much smaller number of heterotrimeric G proteins. Members of the Tetraspanin family organize extensive complexes of cell surface proteins and thus have the potential to act as GPCR scaffolds; however, Tetraspanin-GPCR complexes had not previously been described. We now show that a GPCR, GPR56/TM7XN1, and heterotrimeric G protein subunits, Gαq, Gα11, and Gβ, associate specifically with Tetraspanins and CD81, but not with other Tetraspanins. CD9 Complexes of GPR56 with CD9 and CD81 remained intact when fully solubilized and were resistant to cholesterol depletion. Hence they do not depend on detergent-insoluble, raft-like membrane microdomains for stability. A central role for CD81 in promoting or stabilizing a GPR56-CD81-Gαq/11 complex was revealed by CD81 immunodepletion and reexpression experiments. Finally, antibody engagement of cell surface CD81 or cell activation with phorbol ester revealed two distinct mechanisms by which GPR56-CD81-Gαq/11 complexes can be dynamically regulated. These data reveal a potential role for Tetraspanins CD9 and CD81 as GPCR scaffolding proteins.

Claude Boucheix - One of the best experts on this subject based on the ideXlab platform.

  • Regulation of the trafficking and the function of the metalloprotease ADAM10 by Tetraspanins.
    Biochemical Society Transactions, 2017
    Co-Authors: Julien Saint-pol, Stéphanie Charrin, Claude Boucheix, Etienne Eschenbrenner, Emmanuel Dornier, Eric Rubinstein
    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 Alzheimer9s disease.

  • The Major CD9 and CD81 Molecular Partner
    Journal of Biological Chemistry, 2017
    Co-Authors: Stéphanie Charrin, Franois Le Naour, Michael Oualid, Martine Billard, Gilbert Faure, Claude Boucheix, Samir M. Hanash, Eric Rubinstein
    Abstract:

    By associating with specific partner molecules and with each other, the Tetraspanins are thought to assem- ble multimolecular complexes that may be especially relevant with respect to metastasis. We have previously identified a 135-kDa molecule (CD9P-1) as a major mo- lecular partner of CD9 in cancer cell lines. This molecule was identified, after immunoaffinity purification and mass spectrometry analysis, as the protein encoded by the KIAA1436 gene and the human ortholog of a rat protein known as FPRP. Cross-linking experiments de- tected a complex of the size of CD9 plus CD9P-1, showing that these glycoproteins directly associate with each other, probably in the absence of any other molecule. The use of chimeric CD9/CD82 molecules revealed the role of the second half of CD9, comprising the large extracellular loop and the fourth transmembrane do- main. CD9P-1 was also shown to form separate com- plexes with CD81 and with an unidentified 175-kDa mol- ecule. It also associated with other Tetraspanins under conditions maintaining Tetraspanin/Tetraspanin inter- actions. The identification of a protein strongly linked to the Tetraspanin web and the production of a specific monoclonal antibody will help to further characterize the role of this “web” under physiological and patholog- ical conditions.

  • Tetraspanins at a glance
    Journal of Cell Science, 2014
    Co-Authors: Stéphanie Charrin, Claude Boucheix, Stéphanie Jouannet, Eric Rubinstein
    Abstract:

    Tetraspanins are a family of proteins with four transmembrane domains that play a role in many aspects of cell biology and physiology; they are also used by several pathogens for infection and regulate cancer progression. Many Tetraspanins associate specifically and directly with a limited number of proteins, and also with other Tetraspanins, thereby generating a hierarchical network of interactions. Through these interactions, Tetraspanins are believed to have a role in cell and membrane compartmentalization. In this Cell Science at a Glance article and the accompanying poster, we describe the basic principles underlying Tetraspanin-based assemblies and highlight examples of how Tetraspanins regulate the trafficking and function of their partner proteins that are required for the normal development and function of several organs, including, in humans, the eye, the kidney and the immune system.

  • Targeting Tetraspanins in cancer.
    Expert Opinion on Therapeutic Targets, 2012
    Co-Authors: Mónica Sala-valdés, Eric Rubinstein, Naouel Ailane, Céline Greco, Claude Boucheix
    Abstract:

    Introduction: Tetraspanins are a family of small proteins that cross the membrane four times and form complexes by interacting between themselves and with a variety of transmembrane and cytosolic proteins, building a network of interactions referred to as Tetraspanin web or Tetraspanin enriched microdomains (TEMs). These domains provide a signaling platform involved in many important cellular functions and malignant processes. Areas covered: The authors describe the methods and the rationale for targeting Tetraspanins in the therapy of cancer in this review. Expert opinion: Targeting Tetraspanins in cancer may be a promising therapy due to the importance of Tetraspanins in several steps of tumor formation, communication with the environment, dissemination, and metastasis.

  • Lateral organization of membrane proteins: Tetraspanins spin their web.
    Biochemical Journal, 2009
    Co-Authors: Stéphanie Charrin, Franois Le Naour, Claude Boucheix, Olivier Silvie, Pierre-emmanuel Milhiet, Eric Rubinstein
    Abstract:

    Despite high expression levels at the plasma membrane or in intracellular vesicles, Tetraspanins remain among the most mysterious transmembrane molecules 20 years after their discovery. Several genetic studies in mammals and invertebrates have demonstrated key physiological roles for some of these Tetraspanins, in particular in the immune response, sperm–egg fusion, photoreceptor function and the normal function of certain epithelia. Other studies have highlighted their ability to modulate cell migration and metastasis formation. Their role in the propagation of infectious agents has drawn recent attention, with evidence for HIV budding in Tetraspanin-enriched plasma membrane domains. Infection of hepatocytic cells by two major pathogens, the hepatitis C virus and the malaria parasite, also requires the Tetraspanin CD81. The function of Tetraspanins is thought to be linked to their ability to associate with one another and a wealth of other integral proteins, thereby building up an interacting network or ‘Tetraspanin web’. On the basis of the biochemical dissection of the Tetraspanin web and recent analysis of the dynamics of some of its constituents, we propose that Tetraspanins tightly regulate transient interactions between a variety of molecules and as such favour the efficient assembly of specialized structures upon proper stimulation.

Fedor Berditchevski - One of the best experts on this subject based on the ideXlab platform.

  • Tetraspanins in human epithelial malignancies.
    The Journal of Pathology, 2010
    Co-Authors: Hanna M. Romanska, Fedor Berditchevski
    Abstract:

    Transmembrane proteins of the Tetraspanin superfamily are implicated in a broad spectrum of cellular processes in many biological systems in both health and disease. Tetraspanins form specialized membrane microdomains on the cell surface which control cell proliferation and migration through various adhesion and growth factor receptors. Recent extensive research has shown that expression of various Tetraspanins and their associated partners is deregulated in human malignancies. Although, for the most part, the degree of involvement of Tetraspanins in carcinogenesis remains to be established, increasing evidence suggests that these proteins might be of clinical significance in at least some malignancies. Here we provide a comprehensive review of the existing data on expression of Tetraspanins in breast cancer and other human epithelial tumours, with an emphasis on their value as potential prognostic markers. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • identification of tspan9 as a novel platelet Tetraspanin and the collagen receptor gpvi as a component of Tetraspanin microdomains
    Biochemical Journal, 2009
    Co-Authors: Majd B Protty, Leonie K. Ashman, Nicholas A Watkins, Dario Colombo, Steven G Thomas, Victoria L Heath, John M J Herbert, Roy Bicknell, Yotis A Senis, Fedor Berditchevski
    Abstract:

    Platelets are essential for wound healing and inflammatory processes, but can also play a deleterious role by causing heart attack and stroke. Normal platelet activation is dependent on Tetraspanins, a superfamily of glycoproteins that function as ‘organisers’ of cell membranes by recruiting other receptors and signalling proteins into Tetraspanin-enriched microdomains. However, our understanding of how Tetraspanin microdomains regulate platelets is hindered by the fact that only four of the 33 mammalian Tetraspanins have been identified in platelets. This is because of a lack of antibodies to most Tetraspanins and difficulties in measuring mRNA, due to low levels in this anucleate cell. To identify potentially platelet-expressed Tetraspanins, mRNA was measured in their nucleated progenitor cell, the megakaryocyte, using serial analysis of gene expression and DNA microarrays. Amongst 19 Tetraspanins identified in megakaryocytes, Tspan9, a previously uncharacterized Tetraspanin, was relatively specific to these cells. Through generating the first Tspan9 antibodies, Tspan9 expression was found to be tightly regulated in platelets. The relative levels of CD9, CD151, Tspan9 and CD63 were 100, 14, 6 and 2 respectively. Since CD9 was expressed at 49000 cell surface copies per platelet, this suggested a copy number of 2800 Tspan9 molecules. Finally, Tspan9 was shown to be a component of Tetraspanin microdomains that included the collagen receptor GPVI (glycoprotein VI) and integrin α6β1, but not the von Willebrand receptor GPIbα or the integrins αIIbβ3 or α2β1. These findings suggest a role for Tspan9 in regulating platelet function in concert with other platelet Tetraspanins and their associated proteins.

  • Tetraspanins as regulators of protein trafficking.
    Traffic, 2006
    Co-Authors: Fedor Berditchevski, Elena Odintsova
    Abstract:

    The four transmembrane proteins of the Tetraspanin superfamily are the main structural units of specialised membrane microdomains referred to as Tetraspanin-enriched microdomains, (TERM or TEM). Variations in homotypic and heterotypic interactions within TERM result in the modulation of signalling pathways involving Tetraspanin associated receptors including integrins and receptor tyrosine kinases. It has recently become apparent that, in addition to their purely structural function as organisers of TERM, Tetraspanins also regulate various aspects of trafficking and biosynthetic processing of associated receptors. In this chapter we will specifically focus on this aspect of Tetraspanin function.

  • expression of the palmitoylation deficient cd151 weakens the association of α3β1 integrin with the Tetraspanin enriched microdomains and affects integrin dependent signaling
    Journal of Biological Chemistry, 2002
    Co-Authors: Fedor Berditchevski, Elena Odintsova, Shigeaki Sawada, Elizabeth Gilbert
    Abstract:

    Abstract Transmembrane proteins of the Tetraspanin superfamily are assembled in multimeric complexes on the cell surface. Spatial orientation of Tetraspanins within these complexes may affect signaling functions of the associated transmembrane receptors (e.g. integrins, receptor-type tyrosine kinases). The structural determinants that control assembly of the Tetraspanin complexes are unknown. We have found that various Tetraspanins and the α3 integrin subunit are palmitoylated. The stability and molecular composition of the palmitoylated α3β1-Tetraspanin complexes are not affected by adhesion. To assess the significance of palmitoylation in the function of the α3β1-Tetraspanin complexes we mapped the sites of palmitoylation for CD151. Mutation of six cysteines, Cys11, Cys15, Cys79, Cys80, Cys242, and Cys243 was necessary to completely abolish palmitoylation of CD151. The association of the palmitoylation-deficient mutant of CD151 (CD151Cys8) with CD81 and CD63 was markedly decreased, but the interaction of the α3β1-CD151Cys8 complex with phosphatidylinositol 4-kinase was not affected. Ectopic expression of CD151Cys8 in Rat-1 cells impaired the interactions of the endogenous CD63 and CD81 with the α3β1 integrin. Although the expression of the palmitoylation-deficient CD151 does not change cell spreading on the extracellular matrix, the number of focal adhesions increased. Adhesion-induced phosphorylation of PKB/c-Akt is markedly increased in cells expressing a palmitoylation-deficient mutant, thereby providing direct evidence for the role of the Tetraspanin microdomains in regulation of the integrin-dependent phosphatidylinositol 3-kinase signaling pathway. In contrast, activation of FAK and ERK1/2 were not affected by the expression of CD151Cys8. Our results demonstrate that palmitoylation of Tetraspanins is critical not only for the organization of the integrin-Tetraspanin microdomains but also has a specific role in modulation of adhesion-dependent signaling.