Wednesday, 29th January 2020

Tetraspanin-enriched membrane microdomains in extracellular vesicles and cell adhesion and migration





María Yáñez-Mó







Research summary:

Our group is focused on the characterization of tetraspanin-enriched microdomains (TEMs), specialized membrane platforms involved in cell-cell adhesion and migration processes as reviewed in 2009 in Trends in Cell Biology (2009).


Figure 1: Tetraspanin-enriched microdomains and their functions. It has been demonstrated that TEM-induced clustering or segregation of adhesion receptors and signalling molecules plays a functional role in phenomena related to migration and invasion, intercellular adhesion, membrane fusion events and intracellular trafficking. These phenomena are implicated in several biological processes. From Yáñez-Mó et al., Trends Cell Biol. 2009 Sep;19(9):434-46

We have developed two main lines of research. The first one is devoted to the study of membrane-bound proteases, and how their activity is regulated by their inclusion into TEMs, such as in the case of MT1-MMP/CD151/alpha3beta1 integrin ternary complexes.

A second line of research is devoted to the characterization of tetraspanins intracellular connections. Starting with a high throughput proteomic screen, we thereafter study the relevance of the molecular interactions found, in cellular models for fundamental processes of the biology of the immune system (leukocyte migration, immune synapse formation) or tumor cell motility.


Figure 2: Protein interaction networks for CD81 and EWI-2 ligands identified in human primary lymphoblast-derived exosomes. A, intracellular ligands of CD81 and EWI-2 were manually clustered into groups according to their function using the IPA analysis program. Symbol size is proportional to the number of peptides identified for each protein in the pull-down assays. B, proportions of proteins in exosomes that were identified as ligands of EWI-2 and CD81 in exosomes. The proportions were calculated on the basis of the number of peptides identified per protein in total exosome lysates. From Perez-Hernandez D, Gutiérrez-Vázquez C, Jorge I, López-Martín S, Ursa A, Sánchez-Madrid F, Vázquez J, Yáñez-Mó M. J Biol Chem. 2013 Apr 26;288(17):11649-61


Figure 3: Tetraspanins in extracelular vesicle formation and function. Tetraspanins have the capacity to interact with several receptor and signaling molecules at the membrane, organizing specialized tetraspanin-enriched microdomains (TEMs) that may play a role in (A) EV biogenesis, (B) the selection of exosome cargo (proteins and miRNAs), (C) the binding and uptake of exosomes by target cells, or (D) the ability of exosomes to present antigen in the context of an immune response. From Andreu Z and Yáñez-Mó M. Front Immunol. 2014 Sep 16;5:442. doi: 10.3389/fimmu.2014.00442


Intracellular connections of tetraspanin-enriched microdomains led us also to the field of extracellular vesicle (EV) research, since tetraspanin proteins are among the most abundant proteins on EV. Extracellular vesicles, including microvesicles, ectosomes, shedding vesicles, microparticles and exosomes, represent a novel mechanism of intercellular communication as vehicles for intercellular transfer of functional membrane and cytosolic proteins, lipids, and RNAs.


Relevant publications:

  • Biological properties of extracellular vesicles and their physiological functions. Yáñez-Mó M, Siljander PR, Andreu Z, Zavec AB, Borràs FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, Colás E, Cordeiro-da Silva A, Fais S, Falcon-Perez JM, Ghobrial IM, Giebel B, Gimona M, Graner M, Gursel I, Gursel M, Heegaard NH, Hendrix A, Kierulf P, Kokubun K, Kosanovic M, Kralj-Iglic V, Krämer-Albers EM, Laitinen S, Lässer C, Lener T, Ligeti E, Linē A, Lipps G, Llorente A, Lötvall J, Manček-Keber M, Marcilla A, Mittelbrunn M, Nazarenko I, Nolte-'t Hoen EN, Nyman TA, O'Driscoll L, Olivan M, Oliveira C, Pállinger É, Del Portillo HA, Reventós J, Rigau M, Rohde E, Sammar M, Sánchez-Madrid F, Santarém N, Schallmoser K, Ostenfeld MS, Stoorvogel W, Stukelj R, Van der Grein SG, Vasconcelos MH, Wauben MH, De Wever O.J Extracell Vesicles. 2015 May 14;4:27066. doi: 10.3402/jev.v4.27066. eCollection 2015. PMID: 25979354
  • Tetraspanins in extracellular vesicle formation and function. Andreu Z, Yáñez-Mó M. Front Immunol. 2014 Sep 16;5:442. doi: 10.3389/fimmu.2014.00442. eCollection 2014. Review. PMID: 25278937
  • The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. Perez-Hernandez D, Gutiérrez-Vázquez C, Jorge I, López-Martín S, Ursa A, Sánchez-Madrid F, Vázquez J, Yáñez-Mó M. J Biol Chem. 2013 Apr 26;288(17):11649-61. doi:10.1074/jbc.M112.445304. Epub 2013 Mar 5. PMID: 23463506
  • CD81 regulates cell migration through its association with Rac GTPase. Tejera E, Rocha-Perugini V, López-Martín S, Pérez-Hernández D, Bachir AI, Horwitz AR, Vázquez J, Sánchez-Madrid F, Yáñez-Mo M. Mol Biol Cell. 2013 Feb;24(3):261-73. doi: 10.1091/mbc.E12-09-0642. Epub 2012 Dec 21. PMID: 23264468
  • EWI-2 association with α-actinin regulates T cell immune synapses and HIV viral infection. Gordón-Alonso M, Sala-Valdés M, Rocha-Perugini V, Pérez-Hernández D, López-Martín S, Ursa A, Alvarez S, Kolesnikova TV, Vázquez J, Sánchez-Madrid F, Yáñez-Mó M. J Immunol. 2012 Jul 15;189(2):689-700

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