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Molecular and Cellular Biology, September 2007, p. 5986-6000, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00136-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

WAVE2 Regulates High-Affinity Integrin Binding by Recruiting Vinculin and Talin to the Immunological Synapse{triangledown}

Jeffrey C. Nolz,1 Ricardo B. Medeiros,3 Jason S. Mitchell,3 Peimin Zhu,4 Bruce D. Freedman,4 Yoji Shimizu,3 and Daniel D. Billadeau1,2*

Department of Immunology,1 Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905,2 Department of Laboratory Medicine and Pathology, Center for Immunology, Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota 55455,3 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 191044

Received 22 January 2007/ Returned for modification 12 March 2007/ Accepted 11 June 2007

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.

* Corresponding author. Mailing address: Department of Immunology and Division of Oncology Research, 200 First Street SW, Rochester, MN 55905. Phone: (507) 266-4334. Fax: (507) 266-5146. E-mail: billadeau.daniel{at}mayo.edu

{triangledown} Published ahead of print on 26 June 2007.

Molecular and Cellular Biology, September 2007, p. 5986-6000, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00136-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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