WAVE2 regulates high-affinity integrin binding by recruiting vinculin and talin to the immunological synapse

Jeffrey C. Nolz, Ricardo B. Medeiros, Jason S. Mitchell, Peimin Zhu, Bruce D. Freedman, Yoji Shimizu, Daniel D. Billadeau

Research output: Contribution to journalArticle

74 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5986-6000
Number of pages15
JournalMolecular and cellular biology
Volume27
Issue number17
DOIs
StatePublished - Sep 1 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Nolz, J. C., Medeiros, R. B., Mitchell, J. S., Zhu, P., Freedman, B. D., Shimizu, Y., & Billadeau, D. D. (2007). WAVE2 regulates high-affinity integrin binding by recruiting vinculin and talin to the immunological synapse. Molecular and cellular biology, 27(17), 5986-6000. https://doi.org/10.1128/MCB.00136-07