title: WAVE2 regulates high-affinity integrin binding by recruiting vinculin and talin to the immunological synapse.
abstract: T-cell-receptor (TCR)-mediated integrin activation is required for T-cell-antigen-presenting cell conjugation and adhesion to extracellular matrix components. While it has been demonstrated that the actin cytoskeleton and its regulators play an essential role in this process, no mechanism has been established which directly links TCR-induced actin polymerization to the activation of integrins. Here, we demonstrate that TCR stimulation results in WAVE2-ARP2/3-dependent F-actin nucleation and the formation of a complex containing WAVE2, ARP2/3, vinculin, and talin. The verprolin-connecting-acidic (VCA) domain of WAVE2 mediates the formation of the ARP2/3-vinculin-talin signaling complex and talin recruitment to the immunological synapse (IS). Interestingly, although vinculin is not required for F-actin or integrin accumulation at the IS, it is required for the recruitment of talin. In addition, RNA interference of either WAVE2 or vinculin inhibits activation-dependent induction of high-affinity integrin binding to VCAM-1. Overall, these findings demonstrate a mechanism in which signals from the TCR produce WAVE2-ARP2/3-mediated de novo actin polymerization, leading to integrin clustering and high-affinity binding through the recruitment of vinculin and talin.
authors.affiliation: Department of Immunology and Division of Oncology Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Nolz
authors.forename: Ricardo B
authors.initials: RB
authors.lastname: Medeiros
authors.forename: Jason S
authors.initials: JS
authors.lastname: Mitchell
authors.forename: Peimin
authors.initials: P
authors.lastname: Zhu
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Freedman
authors.forename: Yoji
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000502:physiology; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D046912:Multiprotein Complexes; D017434:Protein Structure, Tertiary; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016608:Talin / Q000378:metabolism*; D016596:Vinculin / Q000378:metabolism*; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D018821:CD18 Antigens; D019012:Integrin beta1; D016169:Lymphocyte Function-Associated Antigen-1; D046912:Multiprotein Complexes; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; D016608:Talin; C496618:VAV1 protein, human; C120152:WASF2 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D016596:Vinculin; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D002118:Calcium