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Tetraspanin functions and associated microdomains

Hemler, Martin E.·2005·Nature Reviews Molecular Cell Biology

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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.

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High-Level Expression, Single-Step Immunoaffinity Purification and Characterization of Human Tetraspanin Membrane Protein CD81
Takayama, H., Chelikani, P., Reeves, P. J., Zhang, S., & Khorana, H. G. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002314 · Cited by 31
“Although tetraspanins are widely distributed, occurring in most animal tissues and have been shown to be involved in essential cellular and physiological functions including cell proliferation, activation and signaling [4,5,7], its detail molecular structure remains largely elusive.”
Background
The evolution of vertebrate tetraspanins: gene loss, retention, and massive positive selection after whole genome duplications
Huang, S., Tian, H., Chen, Z., Yu, T. Y., & Xu, A. (2010) · BMC Evolutionary Biology · doi:10.1186/1471-2148-10-306 · Cited by 33
“These hypotheses may explain the situation of tetraspanins, because tetraspanins are involved in various biological processes and interacting with various proteins at different affinities [13].”
Background
Dynamic and coordinated single‐molecular interactions at TM4SF5‐enriched microdomains guide invasive behaviors in 2‐ and 3‐dimensional environments
Kim, H., Kwon, S., Nam, S. H., Jung, J. W., Kang, M., Ryu, J., Kim, J. E., Cheong, J., Cho, C. Y., Kim, S., et al. (2017) · The FASEB Journal · doi:10.1096/fj.201600944rr · Cited by 31
“TM4SF members interact with themselves, growth factor receptors, Ig superfamilyproteins, signaling enzymes, and integrins, presumably at tetraspanin-enriched microdomains (TERMs) (3).”
BackgroundInfluential
CD82 hypomethylation is essential for tuberculosis pathogenesis via regulation of RUNX1-Rab5/22
Koh, H.-J., Kim, Y.-R., Kim, J., Yun, J.-S., Kim, S., Kim, S. Y., Jang, K., & Yang, C. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0091-4 · Cited by 31
Tetraspanin CD151 and integrin α3β1 contribute to the stabilization of integrin α6β4-containing cell-matrix adhesions
Molder, L. T., Juksar, J., Harkes, R., Wang, W., Kreft, M., & Sonnenberg, A. (2019) · Journal of Cell Science · doi:10.1242/jcs.235366 · Cited by 32
“Incorporation of integrins α6β4 and α3β1 in TEMs is facilitated through binding of their α subunits to CD151 (Hemler, 2005).”
Background
Tetraspanins CD81 and CD82 Facilitate α4β1-Mediated Adhesion of Human Erythroblasts to Vascular Cell Adhesion Molecule-1
Spring, F. A., Griffiths, R. E., Mankelow, T. J., Agnew, C., Parsons, S. F., Chasis, J. A., & Anstee, D. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0062654 · Cited by 34
“There is little evidence for effects of tetraspanin antibodies on the affinity of integrin-mediated adhesion to ligands in static adhesion assays in other cells [29], or on integrinextracellular matrix protein interactions [37].”
Background
Cholesterol lowering drug may influence cellular immune response by altering MHC II function
Roy, K., Ghosh, M., Pal, T. K., Chakrabarti, S., & Roy, S. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m041954 · Cited by 32
Tetraspanins shape the synapse
Murru, L., Moretto, E., Martano, G., & Passafaro, M. (2018) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2018.04.001 · Cited by 31
“Tetraspanins are also able to interact directly with intracellular proteins, such as type II phosphatidylinositol 4-kinases (PI4K) and PKCα and β (Hemler, 2005).”
Promotion of Bone Morphogenetic Protein Signaling by Tetraspanins and Glycosphingolipids
Liu, Z., Shi, H., Szymczak, L. C., Aydin, T., Yun, S., Constas, K., Schaeffer, A., Ranjan, S., Kubba, S., Alam, E., et al. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005221 · Cited by 33
“One novel modulator is TSP-21, which belongs to a family of transmembrane molecules called tetraspanins [24].”
Background
Specific Targeting of Human Inflamed Endothelium and In Situ Vascular Tissue Transfection by the Use of Ultrasound Contrast Agents
Barreiro, O., Aguilar, R., Tejera, E., Megı́as, D., Torres-Alba, F. D., Evangelista, A., & Sánchez‐Madrid, F. (2009) · JACC. Cardiovascular imaging · doi:10.1016/j.jcmg.2009.04.012 · Cited by 31
Regulation of Receptor Tyrosine Kinase Ligand ProcessingPreprint
Adrain, C., & Freeman, M. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008995 · Cited by 31
“The function of tetraspanins is diverse and not well understood in many cases but a common theme is the organization of membrane proteins into defined microdomains (Hemler 2005).”
Background
Roles for HB‐EGF and CD9 in multiple sclerosis
Schenk, G. J., Dijkstra, S., Hof, A. J. V. H., van der Pol, S. M. A., Drexhage, J., van der Valk, P., Reijerkerk, A., van Horssen, J., & de Vries, H. E. (2013) · Glia · doi:10.1002/glia.22565 · Cited by 30
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Toya, S. P., Wary, K. K., Mittal, M., Li, F., Tóth, P. T., Park, C., Rehman, J., & Malik, A. B. (2015) · Stem Cells · doi:10.1002/stem.1974 · Cited by 30
Molecular Characterization of the NADPH Oxidase Complex in the Ergot Fungus Claviceps purpurea : CpNox2 and CpPls1 Are Important for a Balanced Host-Pathogen Interaction
Schürmann, J., Buttermann, D., Herrmann, A., Giesbert, S., & Tudzynski, P. (2013) · Molecular Plant-Microbe Interactions · doi:10.1094/mpmi-03-13-0064-r · Cited by 31
Gene Therapy in Mouse Models of Deafness and Balance Dysfunction
Wang, L., Kempton, J. B., & Brigande, J. V. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00300 · Cited by 30
“Human fetal hearing has been assessed by ultrasound-based detection of startle responses to pure tone stimuli delivered by a loudspeaker placed on the maternal abdomen (Hepper and Shahidullah, 1994).”
BackgroundMethod
Tetraspanin 7 and its closest paralog tetraspanin 6: membrane organizers with key functions in brain development, viral infection, innate immunity, diabetes and cancer
Pérot, B. P., & Ménager, M. M. (2020) · Medical Microbiology and Immunology · doi:10.1007/s00430-020-00681-3 · Cited by 29
CD81 knockout promotes chemosensitivity and disrupts in vivo homing and engraftment in acute lymphoblastic leukemia
Quagliano, A., Gopalakrishnapillai, A., Kolb, E. A., & Barwe, S. P. (2020) · Blood Advances · doi:10.1182/bloodadvances.2020001592 · Cited by 30
Role of Tetraspanins in Hepatocellular Carcinoma
Cai, S., Deng, Y., Peng, H., & Shen, J. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.723341 · Cited by 30
“The structure and function of ECL1 have so far remained unclear (5, 6).”
Background
Tetraspanins CD9 and CD81 are molecular partners of trimeric FcɛRI on human antigen-presenting cells
Peng, W., Yu, C., Kolanus, W., Mazzocca, A., Bieber, T. R. M., Kraft, S., & Novak, N. (2011) · Allergy · doi:10.1111/j.1398-9995.2010.02524.x · Cited by 30
“However, most of the functions of tetraspanins are not related to any typical cell-surface receptor ligand binding, but mediated by lateral interactions with their partner proteins creating a ‘tetraspanin web’ (1).”
BackgroundInfluential
Cysteine Residues in the Large Extracellular Loop (EC2) Are Essential for the Function of the Stress-regulated Glycoprotein M6a
Fuchsová, B., Fernández, M. E., Alfonso, J., & Frasch, A. C. C. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.012377 · Cited by 30
Structural and functional relationships between photoreceptor tetraspanins and other superfamily members
Conley, S. M., Stuck, M. W., & Naash, M. I. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0736-0 · Cited by 30
“Glycosylation has been implicated as a determinant of protein interactions in tetraspanins on a proteinby-protein basis [2].”
BackgroundInfluential
Plasma Membrane Tetraspanin CD81 Complexes with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and Low Density Lipoprotein Receptor (LDLR), and Its Levels Are Reduced by PCSK9
Le, Q.-T., Blanchet, M., Seidah, N. G., & Labonté, P. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.642991 · Cited by 31
“We chose CD9 as a control for CD81 because as members of the tetraspanin family both are present in tetraspanin-enriched microdomains, and their interaction has been proposed previously (48, 49).”
Method
CD9P-1 expression correlates with the metastatic status of lung cancer, and a truncated form of CD9P-1, GS-168AT2, inhibits in vivo tumour growth
Guilmain, W., Colin, S., Legrand, E., Vannier, J., Steverlynck, C., Bongaerts, M., Vasse, M., & Al-Mahmood, S. (2011) · British Journal of Cancer · doi:10.1038/sj.bjc.6606033 · Cited by 29
“…established that tetraspanins associate with each other and with other cell surface proteins and receptors to form functional signalling platforms (Maecker et al, 1997; Boucheix et al, 2001; Boucheix and Rubinstein, 2001; Hemler, 2003, 2005; Tarrant et al, 2003; Yunta and Lazo, 2003; Lazo, 2007).”
Background
Tetraspanins CD9 and CD151, epidermal growth factor receptor and cyclooxygenase-2 expression predict malignant progression in oral epithelial dysplasia
Nankivell, P., Williams, H., McConkey, C., Webster, K., High, A. S., Maclennan, K. A., Şengüven, B., Rabbitts, P. H., & Mehanna, H. M. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.600 · Cited by 29
“The modulatory abilities of these tetraspanins result in changes to tumorigenic processes, such as cell adhesion, motility, invasion, and angiogenesis (Hemler, 2005; Zöller, 2009).”
Background
CD82 controls CpG‐dependent TLR9 signaling
Khan, N. S., Lukason, D. P., Feliu, M., Ward, R., Lord, A. K., Reedy, J. L., Ramirez‐Ortiz, Z. G., Tam, J. M., Kasperkovitz, P. V., Negoro, P. E., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201901547r · Cited by 29
“As their namesuggests,members of this protein family have 4 transmembrane domains, 2 extracellular loops, and short intracellular amino and carboxy termini (1).”
BackgroundMethod
Copper, endoproteolytic processing of the prion protein and cell signalling
Haigh, C. L. (2010) · Frontiers in bioscience · doi:10.2741/3663 · Cited by 29
Distinct MHC Class II Molecules Are Associated on the Dendritic Cell Surface in Cholesterol-dependent Membrane Microdomains
Khandelwal, S., & Roche, P. A. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.147793 · Cited by 29
Molecular view on PRR cross-talk in antifungal immunity
Hontelez, S., Sanecka-Duin, A., Netea, M. G., van Spriel, A. B., & Adema, G. J. (2012) · Cellular Microbiology · doi:10.1111/j.1462-5822.2012.01748.x · Cited by 31
“The tetraspanin family of transmembrane-four proteins have the ability to interact in cis with specific (immune-) receptors, with each other, and with signalling molecules, whereby they form multimolecular complexes, or ‘tetraspanin microdomains’ (Hemler, 2005; Charrin et al., 2009).”
Background
New insights into the tetraspanin Tspan5 using novel monoclonal antibodies
Saint‐Pol, J., Billard, M., Dornier, E., Eschenbrenner, E., Danglot, L., Boucheix, C., Charrin, S., & Rubinstein, E. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.765669 · Cited by 29
CD151, a novel host factor of nuclear export signaling in influenza virus infection
Qiao, Y., Yan, Y., Tan, K. S., Tan, S. S. L., Seet, J. E., Arumugam, T. V., Chow, V. T. K., Wang, D. Y., & Tran, T. (2017) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2017.11.032 · Cited by 28
Isolation and characterisation of CD9-positive pituitary adult stem/progenitor cells in rats
Horiguchi, K., Fujiwara, K., Yoshida, S., Nakakura, T., Arae, K., Tsukada, T., Hasegawa, R., Takigami, S., Ohsako, S., Yashiro, T., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-23923-0 · Cited by 29
α2β1 integrin controls association of Rac with the membrane and triggers quiescence of endothelial cells
Cailleteau, L., Estrach, S., Thyss, R., Boyer, L., Doye, A., Domange, B., Johnsson, N., Rubinstein, E., Boucheix, C., Ebrahimian, T. G., et al. (2010) · Journal of Cell Science · doi:10.1242/jcs.058875 · Cited by 28
Tetraspanin CD151 as an emerging potential poor prognostic factor across solid tumors: a systematic review and meta-analysis
Zeng, P., Wang, Y.-H., Si, M., Gu, J., Li, P., Lu, P., & Chen, M. (2016) · Oncotarget · doi:10.18632/oncotarget.13532 · Cited by 28
“Expression of CD151 was observed in different cell types [1].”
Background
Overexpressed Receptors and Proteins in Lung Cancer
Gorain, B., Bhattamisra, S. K., Choudhury, H., Nandi, U., Pandey, M., & Kesharwani, P. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-815720-6.00003-4 · Cited by 28
CD9 blockade suppresses disease progression of high-risk pediatric B-cell precursor acute lymphoblastic leukemia and enhances chemosensitivity
Leung, K. T., Zhang, C., Chan, K. Y. Y., Li, K., Cheung, J. T. K., Ng, M. H. L., Zhang, X., Sit, T., Lee, W., Kang, W., et al. (2019) · Leukemia · doi:10.1038/s41375-019-0593-7 · Cited by 30
“CD9, a tetraspanin family protein, regulates various physiologic processes such as cell motility, adhesion and signaling [9].”
Background
Genetically Engineered Extracellular Vesicles Harboring Transmembrane Scaffolds Exhibit Differences in Their Size, Expression Levels of Specific Surface Markers and Cell-Uptake
Zhang, J., Brown, A. K., Johnson, B., Diebold, D., Asano, K., Marriott, G., & Lü, B. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14122564 · Cited by 32
Exosomes: Nomenclature, Isolation, and Biological Roles in Liver Diseases
Park, S. H., Lee, E. K., Yim, J., Lee, M. H., Lee, E., Lee, Y., & Seo, W. (2023) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2022.161 · Cited by 29
“…membrane fusion (annexins I, II, IV, V, and VI; Rab5; Rab7; Rabp1B; and RabGDI), heat shock proteins (Hsc70, and Hsp90), ESCRT complex proteins (Alix and TSG101), and cytoskeletal proteins (actin, cofilin, tubulin, and moesin) are commonly identified in exosomes (Hemler, 2005; Keller et al., 2007).”
Background
Knockout of the tetraspanin Cd9 in the TRAMP model of de novo prostate cancer increases spontaneous metastases in an organ-specific manner
Copeland, B. T., Bowman, M. J., Boucheix, C., & Ashman, L. K. (2013) · International Journal of Cancer · doi:10.1002/ijc.28204 · Cited by 28
Tetraspanin CD9 is involved in the migration of retinal microvascular endothelial cells
Kuhn, E.-M., Lang, G. E., Deißler, H., & Deissler, H. L. (2007) · International Journal of Molecular Medicine · doi:10.3892/ijmm.20.5.643 · Cited by 28
“Members of this protein family are implicated in various cell types in the regulation of differentiation and fundamental processes including proliferation, adhesion and motility (1,2).”
Down-regulation of TM4SF is associated with the metastatic potential of gastric carcinoma TM4SF members in gastric carcinoma
Chen, Z., Gu, S., Trojanowicz, B., Liu, N., Zhu, G., Dralle, H., & Hoang‐Vu, C. (2011) · World Journal of Surgical Oncology · doi:10.1186/1477-7819-9-43 · Cited by 28
“Previous reports demonstrated that the effects of CD63 on motility were similar to those reported for CD9 and both proteins were reported to associate with b1 and b3 integrins and to be identical with motility-related protein [36].”
BackgroundResult
Glycoprotein M6B Interacts with TβRI to Activate TGF-β-Smad2/3 Signaling and Promote Smooth Muscle Cell Differentiation
Zhang, X., Xie, H., Chang, P., Zhao, H., Xia, Y., Zhang, L., Guo, X., Huang, C., Yan, F., Hu, L., et al. (2018) · Stem Cells · doi:10.1002/stem.2938 · Cited by 28
TM4SF1 involves in miR-1-3p/miR-214-5p-mediated inhibition of the migration and proliferation in keloid by regulating AKT/ERK signaling
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Probing the interaction of tetraspanin CD151 with integrin α3β1 using a panel of monoclonal antibodies with distinct reactivities toward the CD151–integrin α3β1 complex
Yamada, M., Tamura, Y., Sanzen, N., Nishiuchi, R., Hasegawa, H., Ashman, L. K., Rubinstein, E., Yáñez‐Mó, M., Sánchez‐Madrid, F., & Sekiguchi, K. (2008) · Biochemical Journal · doi:10.1042/bj20071625 · Cited by 27
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Mani, B., Agarwal, M., & Katiyar‐Agarwal, S. (2015) · Frontiers in Plant Science · doi:10.3389/fpls.2015.01088 · Cited by 27
“Potential association of tetraspanin with other partners such as immunoglobulin superfamily proteins, proteases, signaling enzymes, GPCRs, cadherins, and proteoglycans has been hypothesized (Hemler, 2005).”
BackgroundInfluential
Role of TSPAN9 in Alphavirus Entry and Early Endosomes
Stiles, K. M., & Kielian, M. C. (2016) · Journal of Virology · doi:10.1128/jvi.00018-16 · Cited by 29
“What might the role of TSPAN9 in the endosomal compartment be? Tetraspanin family proteins are known to create tetraspanin-enriched microdomains consisting of oligomers of tetraspanins and their cis-interacting partner proteins (14).”
Background
TSPAN5 Enriched Microdomains Provide a Platform for Dendritic Spine Maturation through Neuroligin-1 Clustering
Moretto, E., Longatti, A., Murru, L., Chamma, I., Sessa, A., Zapata, J., Hosy, E., Sainlos, M., Saint‐Pol, J., Rubinstein, E., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.09.051 · Cited by 28
“This domain is key for many tetraspanin interactions (Hemler, 2005), and it was previously found to bind ADAM-10 via the residues R135DD137 and N165IYF168.”
BackgroundInfluential
CD81 extracted in SMALP nanodiscs comprises two distinct protein populations within a lipid environment enriched with negatively charged headgroups
Ayub, H., Clare, M., Milic, I., Chmel, N. P., Böning, H., Devitt, A., Krey, T., Bill, R. M., & Rothnie, A. J. (2020) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2020.183419 · Cited by 27
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Extracellular Vesicles as Promising Carriers in Drug Delivery: Considerations from a Cell Biologist’s Perspective
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“ESCRT-independent EXO are instead enriched in tetraspanins, in particular CD9, CD63, CD81, that orchestrate the formation of the tetraspanin-enriched microdomains (TEMS) in the plasma membrane [10,11] and in ceramide, a simple sphingolipid (SL), which plays a critical role in membrane biogenesis [12].”
Background
Correlations between Transmembrane 4 L6 Family Member 5 (TM4SF5), CD151, and CD63 in Liver Fibrotic Phenotypes and Hepatic Migration and Invasive Capacities
Kang, M., Ryu, J., Lee, D., Lee, M.-S., Kim, H., Nam, S. H., Song, H. E., Choi, J., Lee, G.-H., Kim, T. Y., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0102817 · Cited by 27
“Tetraspanins are located in TEMs and are involved in cellular adhesion, migration, and invasion via homophilic and/or heterophilic interactions among the tetraspanins, integrins, and growth factor receptors [25].”
Background
Protein mobilities and P-selectin storage in Weibel–Palade bodies
Kiskin, N. I., Hellen, N., Babich, V., Hewlett, L. J., Knipe, L., Hannah, M. J., & Carter, T. D. (2010) · Journal of Cell Science · doi:10.1242/jcs.073593 · Cited by 27
“Alternatively, it could reflect CD63 oligomerisation, weak binding or steric interactions with cytosolic or WPB core elements (Hemler, 2005; Pols and Klumperman, 2009).”
Background
Regulation of NK cell trafficking by CD81
Krämer, B., Schulte, D., Körner, C., Zwank, C., Hartmann, A., Michalk, M., Söhne, J., Langhans, B., Nischalke, H. D., Coenen, M., et al. (2009) · European Journal of Immunology · doi:10.1002/eji.200939234 · Cited by 27
The Sur7 protein resides in punctate membrane subdomains and mediates spatial regulation of cell wall synthesis inCandida albicans
Álvarez, F. J., Douglas, L. M., & Konopka, J. B. (2009) · Communicative & Integrative Biology · doi:10.4161/cib.7478 · Cited by 27
Effect of expressional alteration of KAI1 on breast cancer cell growth, adhesion, migration and invasion.
Malik, F. A., Sanders, A. J., Kayani, M. A., & Jiang, W. G. (2009) · PubMed · Cited by 27
The Tetraspanin TSPAN33 Controls TLR-Triggered Macrophage Activation through Modulation of NOTCH Signaling
Ruiz‐García, A., López‐López, S., Garcı́a-Ramı́rez, J. J., Baladrón, V., Ruiz‐Hidalgo, M. J., Lopez‐Sanz, L., Ballesteros, Á., Laborda, J., Monsalve, E. M., & Díaz-Guerrá, M. J. M. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1600421 · Cited by 28
Antibody-Mediated Inhibition of Tspan12 Ameliorates Vasoproliferative Retinopathy Through Suppression of β-Catenin Signaling
Bucher, F., Zhang, D., Aguilar, E., Sakimoto, S., Diaz‐Aguilar, M. S., Rosenfeld, M., Zha, Z., Zhang, H., Friedlander, M., & Yea, K. (2017) · Circulation · doi:10.1161/circulationaha.116.025604 · Cited by 28
Regulation of Fibrotic Processes in the Liver by ADAM Proteases
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“Tspans have the ability to form large interacting networks, the so-called tetraspanin-enriched membrane microdomains (TEM) which represent a signalling platform similar to lipid rafts [21].”
Background
The Tetraspanin CD53 Regulates Early B Cell Development by Promoting IL-7R Signaling
Greenberg, Z. J., Monlish, D. A., Bartnett, R. L., Yang, Y., Shen, G., Li, W., Bednarski, J. J., & Schuettpelz, L. G. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1900539 · Cited by 27
“Tetraspanins are known to regulate and interact with surface proteins important for plasma membrane organization and cellular migration and adhesion and, as a family, have been highly studied for their importance during cancer metastasis (17, 31).”
Background
Early-life stress triggers long-lasting organismal resilience and longevity via tetraspanin
Jiang, W. I., Belly, H. D., Wang, B., Wong, A., Kim, M., Oh, F., DeGeorge, J., Huang, X., Guang, S., Weiner, O. D., et al. (2024) · Science Advances · doi:10.1126/sciadv.adj3880 · Cited by 26
Fungal extracellular vesicles mediate cross-kingdom trafficking of virulence effectors into plant cells to promote infection
Wang, Z., Li, W., Kang, G., Deng, J., Qin, S., & Cai, Q. (2025) · Molecular Plant · doi:10.1016/j.molp.2025.07.009 · Cited by 29
Molecular insights into a tetraspanin in the hydatid tapeworm Echinococcus granulosus
Hu, D., Song, X., Xie, Y., Zhong, X., Wang, N., Zheng, Y., Gu, X., Wang, T., Peng, X., & Yang, G. (2015) · Parasites & Vectors · doi:10.1186/s13071-015-0926-y · Cited by 26
“Tetraspanins are transmembrane proteins widely distributed in eukaryotic organisms [37], involved in many cell biological processes [38, 39], and that interact with immune molecules from hosts [40], especially specific molecules such as the major histocompatibility complex (MHC) II [41, 42].”
Background
Identification of novel genes involved in gastric carcinogenesis by suppression subtractive hybridization
Mottaghi-Dastjerdi, N., Soltany‐Rezaee‐Rad, M., Sepehrizadeh, Z., Roshandel, G., Ebrahimifard, F., & Setayesh, N. (2014) · Human & Experimental Toxicology · doi:10.1177/0960327114532386 · Cited by 26
Urinary biomarkers for lupus nephritis: the role of the vascular cell adhesion molecule-1
Gasparin, A. A., de Andrade, N. P. B., Hax, V., Tres, G. L., Veronese, F. V., & Monticielo, O. A. (2019) · Lupus · doi:10.1177/0961203319826695 · Cited by 26
The Context-Dependent Impact of Integrin-Associated CD151 and Other Tetraspanins on Cancer Development and Progression: A Class of Versatile Mediators of Cellular Function and Signaling, Tumorigenesis and Metastasis
Erfani, S. F., Hua, H., Pan, Y.-Y., Zhou, B., & Yang, X.-W. H. (2021) · Cancers · doi:10.3390/cancers13092005 · Cited by 20
“Moreover, the TEM assembly may involve multiple intracellular membrane compartments, such as endoplasmic reticulum, Golgi, lysosomal, endosomal and multivesicular bodies, which have been extensively described by multiple reviews [10,20,21].”
BackgroundInfluential
Kinetics and interaction studies of anti-tetraspanin antibodies and ICAM-1 with extracellular vesicle subpopulations using continuous flow quartz crystal microbalance biosensor
Liangsupree, T., Multia, E., Forssén, P., Fornstedt, T., & Riekkola, M. (2022) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2022.114151 · Cited by 27
Crystal structure of the Tspan15 LEL domain reveals a conserved ADAM10 binding site
Lipper, C. H., Gabriel, K.-H., Seegar, T. C. M., Dürr, K. L., Tomlinson, M. G., & Blacklow, S. C. (2021) · Structure · doi:10.1016/j.str.2021.10.007 · Cited by 26
Accumulation of misfolded SOD1 outlines distinct patterns of motor neuron pathology and death during disease progression in a SOD1G93A mouse model of amyotrophic lateral sclerosis
Salvany, S., Casanovas, A., Piedrafita, L., Gras, S., Calderó, J., & Esquerda, J. E. (2022) · Brain Pathology · doi:10.1111/bpa.13078 · Cited by 26
“Flotillin and CD81 are members of the tetraspanin family that regulate membrane morphology and dynamics, affecting intracellular trafficking, exocytosis-endocytosis, and intercellular signaling [131] that are also recognized as markers for EVs [65].”
Background
Pathogenic myelin-specific antibodies in multiple sclerosis target conformational proteolipid protein 1–anchored membrane domains
Owens, G. P., Fellin, T. J., Matschulat, A. M., Salas, V., Schaller, K., Given, K. S., Ritchie, A. M., Navarro, A., Blauth, K., Hughes, E. G., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci162731 · Cited by 27
“PLP1 is a distant member of the tetraspanin family of proteins, molecules known for molecular organization at the cell membrane (32).”
CD9 is a novel marker for plasma cell precursors in human germinal centers
Yoon, S.-O., Zhang, X., Lee, I. Y., Spencer, N. D., Vo, P., & Choi, Y. S. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.12.102 · Cited by 26
“Tetraspanins organize transmembrane proteins and signaling molecules into functional microdomains in the plasma membrane, regulating fundamental cellular processes such as migration, proliferation, and differentiation [1,2].”
Background
CD9 negatively regulates integrin αIIbβ3 activation and could thus prevent excessive platelet recruitment at sites of vascular injury
Mangin, P., Kleitz, L., Boucheix, C., Gachet, C., & Lanza, F. (2009) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2009.03322.x · Cited by 26
CD151 is associated with prostate cancer cell invasion and lymphangiogenesis in vivo
Detchokul, S., Newell, B., Williams, E. D., & Frauman, A. G. (2013) · Oncology Reports · doi:10.3892/or.2013.2823 · Cited by 26
Tetraspanin-interacting protein IGSF8 is dispensable for mouse fertility
Inoue, N., Nishikawa, T., Ikawa, M., & Okabe, M. (2012) · Fertility and Sterility · doi:10.1016/j.fertnstert.2012.04.029 · Cited by 26
A Post-Entry Role for CD63 in Early HIV-1 Replication
Li, G.-Y., Dziuba, N., Friedrich, B. M., Murray, J., & Ferguson, M. (2011) · Virology · doi:10.1016/j.virol.2011.01.017 · Cited by 35
“CD63 is a type II cellular membrane protein and belongs to the tetraspanin superfamily (Stipp et al., 2003; Hemler, 2005).”
Background
Tetraspanins in Mast Cells
Köberle, M., Kaesler, S., Kempf, W., Wölbing, F., & Biedermann, T. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00106 · Cited by 26
“By spatial enrichment of their binding partners, they bring together interacting elements of signaling pathways and also cluster homotypic signaling, thus amplifying signaling amplitudes (Hemler, 2005; Yanez-Mo et al., 2009).”
Background
Retroviral Env Glycoprotein Trafficking and Incorporation into Virions
Murakami, T. (2012) · Molecular Biology International · doi:10.1155/2012/682850 · Cited by 30
“Another membrane microdomain for retrovirus assembly is the "tetraspanin-enriched microdomain (TEM)" [151] [152] [153] [154] .”
Background
Measles virus M protein-driven particle production does not involve the endosomal sorting complex required for transport (ESCRT) system
Salditt, A., Koethe, S., Pohl, C., Harms, H., Kolesnikova, L., Becker, S., & Schneider‐Schaulies, S. (2010) · Journal of General Virology · doi:10.1099/vir.0.018523-0 · Cited by 26
Distorted leukocyte migration, angiogenesis, wound repair and metastasis in Tspan8 and Tspan8/CD151 double knockout mice indicate complementary activities of Tspan8 and CD51
Zhao, K., Erb, U., Hackert, T., Zöller, M., & Yue, S. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2017.11.007 · Cited by 26
Tspan15 Is a New Stemness‐Related Marker in Hepatocellular Carcinoma
Sidahmed‐Adrar, N., Ottavi, J., Benzoubir, N., Saadi, T. A., Saleh, M. B., Mauduit, P., Guettier, C., Desterke, C., & Naour, F. L. (2019) · PROTEOMICS · doi:10.1002/pmic.201900025 · Cited by 26
Tetraspanin 5 orchestrates resilience to salt stress through the regulation of ion and reactive oxygen species homeostasis in rice
Mani, B., Kaur, I., Dhingra, Y., Saxena, V., Krishna, G. K., Kumar, R., Chinnusamy, V., Agarwal, M., & Katiyar‐Agarwal, S. (2024) · Plant Biotechnology Journal · doi:10.1111/pbi.14476 · Cited by 25
“In animals, tetraspanins are present in various membrane environments, including the plasma membrane, endosomes and ER, where they facilitate intercellular communication and detect environmental stimuli (Hemler, 2005; van Deventer et al ., 2017; Wang et al ., 2012).”
Gamete membrane microdomains and their associated molecules in fertilization signaling
Hasan, A., Fukami, Y., & Sato, K. (2011) · Molecular Reproduction and Development · doi:10.1002/mrd.21336 · Cited by 25
Molecular Crosstalk between the Hepatitis C Virus and the Extracellular Matrix in Liver Fibrogenesis and Early Carcinogenesis
Reungoat, E., Grigorov, B., Zoulim, F., & Pécheur, E. (2021) · Cancers · doi:10.3390/cancers13092270 · Cited by 27
“Recently, we identified the heparan sulfate proteoglycan (HSPG) syndecan-1 as a cofactor of CD81 for HCV entry [31]; both molecules form a complex linking the ECM to the cytoskeleton [40] and integrins, receptors of ECM components [41].”
Background
Tetraspanin-5–mediated MHC class I clustering is required for optimal CD8 T cell activation
Colbert, J. D., Cruz, F. M., Baer, C. E., & Rock, K. L. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2122188119 · Cited by 25
New iron export pathways acting via holo-ferritin secretion
Yanatori, I., Kishi, F., & Toyokuni, S. (2023) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2023.109737 · Cited by 28
Expression and Subcellular Distribution of GFP-Tagged Human Tetraspanin Proteins in Saccharomyces cerevisiae
Skaar, K., Korza, H. J., Tarry, M. J., Sekyrová, P., & Högbom, M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0134041 · Cited by 25
“The first level commonly consists of tightly associated homo-oligomers [26].”
Background
Permissivity of the NCI-60 cancer cell lines to oncolytic Vaccinia Virus GLV-1h68
Ascierto, M. L., Worschech, A., Yu, Z., Adams, S. D., Reinboth, J., Chen, N. G., Pós, Z., Roychoudhuri, R., Pasquale, G. D., Bedognetti, D., et al. (2011) · BMC Cancer · doi:10.1186/1471-2407-11-451 · Cited by 25
“The association between integrins and tetraspanins is common within cells [30] and it has been implicated in adenoviral replication and internalization [31,32] allowing Adenoviral replication even in cell lines lacking adenovirus receptor [33].”
Background
Integrin α3β1 Signaling through MEK/ERK Determines Alternative Polyadenylation of the MMP-9 mRNA Transcript in Immortalized Mouse Keratinocytes
Missan, D. S., Mitchell, K., Subbaram, S., & DiPersio, C. M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119539 · Cited by 26
“Many pro-tumorigenic functions of α3β1 may be controlled through lateral association with the tetraspanin family member, CD151, which occurs within tetraspanin-enriched microdomains on the cell surface [68–70].”
Background
Cross-talk between Tetraspanin CD9 and Transmembrane Adaptor Protein Non-T Cell Activation Linker (NTAL) in Mast Cell Activation and Chemotaxis
Hálová, I., Dráberová, L., Bambousková, M., Machyna, M., Stegurová, L., Smrž, D., & Dráber, P. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.449231 · Cited by 25
“Although tetraspanins are involved in a variety of biological and pathological processes (27, 28), it is not clear whether tetraspanins interact with TRAPs and what are consequences of such interactions.”
Background
Coevolution of Positively Selected IZUMO1 and CD9 in Rodents: Evidence of Interaction Between Gamete Fusion Proteins?1
Vicens, A., & Roldán, E. R. S. (2014) · Biology of Reproduction · doi:10.1095/biolreprod.113.116871 · Cited by 25
Tetraspanin CD151 and integrin α6β1 mediate platelet‐enhanced endothelial colony forming cell angiogenesis
Huang, Z., Miao, X., Patarroyo, M. E., Nilsson, G. P., Pernow, J., & Li, N. (2016) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.13248 · Cited by 25
Tumor suppressor miR‐139‐5p targets Tspan3 and regulates the progression of acute myeloid leukemia through the PI3K/Akt pathway
Zhang, R., Tang, P., Wang, F., Xing, Y., Jiang, Z., Chen, S., Meng, X.-L., Liu, L., Cao, W., Zhao, H., et al. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.27728 · Cited by 25
“The tetraspanin (tetraspan or TM4SF) family forms a large crowd of integral membrane proteins sharing 4 transmembrane helices, including 33 known mammalian cell type–specific members, which participates in forming plasma membrane signaling complexes.(16) Proteins of the tetraspanin family have been found to be implica…”
Background
Dendritic Cells Potently Purge Latent HIV-1 Beyond TCR-Stimulation, Activating the PI3K-Akt-mTOR Pathway
van Montfort, T., van der Sluis, R. M., Darcis, G., Beaty, D. E., Groen, K., Pasternak, A. O., Pollakis, G. P., Vink, M. A., Westerhout, E. M., Hamdi, M., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2019.02.014 · Cited by 25
“negatively influences the RAS activation pathway [22].”
Background
C-type lectin-like receptor 2 (CLEC-2)-dependent DC migration is controlled by tetraspanin CD37
de Winde, C. M., Matthews, A. L., van Deventer, S. J., van der Schaaf, A., Tomlinson, N., Jansen, E., Eble, J. A., Nieswandt, B., McGettrick, H. M., Figdor, C. G., et al. (2018) · Journal of Cell Science · doi:10.1242/jcs.214551 · Cited by 26
“TEMs, also referred to as the tetraspanin web, are formed by the interaction of tetraspanins, a family of four-transmembrane proteins, with each other and partner proteins (Charrin et al., 2009; Hemler, 2005; Levy and Shoham, 2005; Zimmerman et al., 2016; Zuidscherwoude et al., 2015).”
Background
Classes of non-conventional tetraspanins defined by alternative splicing
Hochheimer, N., Sies, R., Aschenbrenner, A. C., Schneider, D., & Lang, T. (2019) · Scientific Reports · doi:10.1038/s41598-019-50267-0 · Cited by 25
miR-216a-mediated upregulation of TSPAN1 contributes to pancreatic cancer progression via transcriptional regulation of ITGA2.
Wang, S., Liu, X., Khan, A. A., Li, H., Tahir, M., Yan, X., Wang, J., & Huang, H. (2020) · PubMed Central · Cited by 25
Native DGC structure rationalizes muscular dystrophy-causing mutations
Liu, S., Su, T., Xia, X., & Zhou, H. Z. (2024) · Nature · doi:10.1038/s41586-024-08324-w · Cited by 26
“8, partner-binding tetraspanin), which is recognized as a ‘molecular facilitator’ for its capacity to cluster and organize TM protein complexes 64–66 .”
Preventive Role of Tetraspanin CD9 in Systemic Inflammation of Chronic Obstructive Pulmonary Disease
Takeda, Y., Suzuki, M., Jin, Y., & Tachibana, I. (2015) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2015-0122tr · Cited by 23
“In general, reported phenotypes of single tetraspanin deletion have been relatively mild, probably due to redundancy and functional compensation among tetraspanins (44).”
Background
Usher syndrome: a review of the clinical phenotype, genes and therapeutic strategies
Toms, M., Bitner-Glindzicz, M. A. K., Webster, A. R., & Moosajee, M. (2015) · Expert Review of Ophthalmology · doi:10.1586/17469899.2015.1033403 · Cited by 27
“Clarin-1 belongs to a superfamily of four-transmembrane-domain proteins (TM4SF), which includes the claudin and tetraspanin families [88].”
Background
Nuclear translocation of the 4-pass transmembrane protein Tspan8
Huang, Y., Li, J., Du, W., Li, S., Li, Y., Qu, H., Xv, J., Yu, L., Zhu, R., & Wang, H. (2021) · Cell Research · doi:10.1038/s41422-021-00522-9 · Cited by 24
TSPAN31 regulates the proliferation, migration, and apoptosis of gastric cancer cells through the METTL1/CCT2 pathway
Ma, X., Qiu, S., Tang, X., Song, Q., Wang, P., Wang, J., Xia, Q., Wang, Z., Zhao, Q., & Lu, M. (2022) · Translational Oncology · doi:10.1016/j.tranon.2022.101423 · Cited by 24
The Tetraspanin CD81 Is a Host Factor for Chikungunya Virus Replication
Laßwitz, L., Belinchón, F. J. Z., Moeller, R. A., Hülskötter, K., Laurent, T., Carlson, L. A., Goffinet, C., Simmons, G., Baumgärtner, W., & Gerold, G. (2022) · mBio · doi:10.1128/mbio.00731-22 · Cited by 24

Authors: Hemler, M. E.
Affiliations: Harvard University (US)
Corresponding author: Hemler, Martin E.
ORCID: Hemler, Martin E.
Venue: Nature Reviews Molecular Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2005-10
Volume: 6
Issue: 10
Pages: 801-811
ISSN: 1471-0072 (ISSN-L)
1471-0080
DOI: 10.1038/nrm1736
OpenAlex: W2063186096
Cited by: 1,355
References: 122
Citations by year: 2026: 38 · 2025: 52 · 2024: 67 · 2023: 60 · 2022: 55 · 2021: 77 · 2020: 80 · 2019: 57 · 2018: 69 · 2017: 67 · 2016: 64 · 2015: 65 · 2014: 73 · 2013: 82 · 2012: 74
FWCI: 5.25
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Reviews Molecular Cell Biology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Bone and Dental Protein Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords: tetraspanins, cell surface proteins, signal transduction, cell motility, cell adhesion, membrane protein regulation, genetic evidence
MeSH terms: Animals, Cell Movement, Humans, Membrane Glycoproteins, Signal Transduction, Membrane Microdomains

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Tetraspanin functions and associated microdomains

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