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Published online
doi:10.1083/jcb.200801121
The Journal of Cell Biology, Vol. 182, No. 6, 1231-1244
The Rockefeller University Press, 0021-9525 $30.00
© Nolz et al.
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Article

The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL–C3G-mediated activation of Rap1



Jeffrey C. Nolz1, Lucas P. Nacusi2, Colin M. Segovis1, Ricardo B. Medeiros3, Jason S. Mitchell3, Yoji Shimizu3, and Daniel D. Billadeau1,2

1 Department of Immunology and 2 Division of Oncology Research, College of Medicine, Mayo Clinic, Rochester, MN 55905
3 Department of Laboratory Medicine and Pathology, Center for Immunology, Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455

Correspondence to Daniel D. Billadeau: billadeau.daniel{at}mayo.edu

WAVE2 regulates T cell receptor (TCR)–stimulated actin cytoskeletal dynamics leading to both integrin clustering and affinity maturation. Although WAVE2 mediates integrin affinity maturation by recruiting vinculin and talin to the immunological synapse in an Arp2/3-dependent manner, the mechanism by which it regulates integrin clustering is unclear. We show that the Abl tyrosine kinase associates with the WAVE2 complex and TCR ligation induces WAVE2-dependent membrane recruitment of Abl. Furthermore, we show that WAVE2 regulates TCR-mediated activation of the integrin regulatory guanosine triphosphatase Rap1 via the recruitment and activation of the CrkL–C3G exchange complex. Moreover, we demonstrate that although Abl does not regulate the recruitment of CrkL–C3G into the membrane, it does affect the tyrosine phosphorylation of C3G, which is required for its guanine nucleotide exchange factor activity toward Rap1. This signaling node regulates not only TCR-stimulated integrin clustering but also affinity maturation. These findings identify a previously unknown mechanism by which the WAVE2 complex regulates TCR signaling to Rap1 and integrin activation.

Abbreviations used in this paper: APC, antigen-presenting cell; GBD, GTPase binding domain; GEF, guanine nucleotide exchange factor; IL-2, interleukin-2; IS, immunological synapse; SMAC, supramolecular activation complex; TCR, T cell receptor.

© 2008 Nolz et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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