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Molecular and Cellular Biology, March 2005, p. 2227-2241, Vol. 25, No. 6
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.6.2227-2241.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Removal of C-Terminal Src Kinase from the Immune Synapse by a New Binding Protein

Souad Rahmouni,1,{dagger} Torkel Vang,1 Andres Alonso,1,{ddagger} Scott Williams,1 Marianne van Stipdonk,2 Chiara Soncini,3 Michel Moutschen,4 Stephen P. Schoenberger,2 and Tomas Mustelin1*

Program of Inflammation, Infectious and Inflammatory Disease Center, and Program of Signal Transduction, Cancer Center, The Burnham Institute, La Jolla,1 Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, California,2 Pharmacia Corporation, Discovery Research Oncology, Nerviano, Italy,3 Unité Métabolique, University of Liège, Liège, Belgium4

Received 2 September 2004/ Returned for modification 20 October 2004/ Accepted 10 December 2004

The Csk tyrosine kinase negatively regulates the Src family kinases Lck and Fyn in T cells. Engagement of the T-cell antigen receptor results in a removal of Csk from the lipid raft-associated transmembrane protein PAG/Cbp. Instead, Csk becomes associated with an ~72-kDa tyrosine-phosphorylated protein, which we identify here as G3BP, a phosphoprotein reported to bind the SH3 domain of Ras GTPase-activating protein. G3BP reduced the ability of Csk to phosphorylate Lck at Y505 by decreasing the amount of Csk in lipid rafts. As a consequence, G3BP augmented T-cell activation as measured by interleukin-2 gene activation. Conversely, elimination of endogenous G3BP by RNA interference increased Lck Y505 phosphorylation and reduced TCR signaling. In antigen-specific T cells, endogenous G3BP moved into a intracellular location adjacent to the immune synapse, but deeper inside the cell, upon antigen recognition. Csk colocalization with G3BP occurred in this "parasynaptic" location. We conclude that G3BP is a new player in T-cell-antigen receptor signaling and acts to reduce the amount of Csk in the immune synapse.

* Corresponding author. Mailing address: The Burnham Institute, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 713-6270. Fax: (858) 713-6274. E-mail: tmustelin{at}burnham-inst.org.

{dagger} Present address: Anatomie et Cytologie Pathologiques, University of Liège, Liège, Belgium.

{ddagger} Present address: Universidad de Valladolid, Instituto de Biologia y Genetica Molecular, Facultad de Medicina, Valladolid, Spain.

Molecular and Cellular Biology, March 2005, p. 2227-2241, Vol. 25, No. 6
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.6.2227-2241.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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