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Molecular and Cellular Biology, April 2003, p. 2515-2529, Vol. 23, No. 7
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.7.2515-2529.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells

Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670,¹ Laboratory of Cytokine Signaling,² Laboratory of Cell Signaling, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa 230-0045,⁶ Department of Molecular Oncology, Graduate School of Medicine,³ Department of Developmental Immunology, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan,⁵ Department of Medical Biophysics, and Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8⁴

Received 23 September 2002/ Returned for modification 28 October 2002/ Accepted 14 January 2003

A docking protein, Gab2, is recruited to the vicinity of the TCR complex and inhibits downstream signaling by interaction with negative regulators. However, the molecular mechanisms of this recruitment remain unclear. We have found that Gab2 associates with LAT upon TCR stimulation and that LAT is essential for Gab2 phosphorylation. By analysis of several Gab2 mutants, the c-Met binding domain (MBD) of Gab2 was found to be both necessary and sufficient for stimulation-induced LAT binding. Within the MBD domain, a novel Grb2 SH3 binding motif, PXXXR, is critical for constitutive association with Gads/Grb2. Through this association, Gab2 is recruited to the lipid raft after TCR ligation and exerts inhibitory function. The in vivo significance of this association is illustrated by the fact that T-cell responses are impaired in transgenic mice expressing wild-type Gab2 but not in mice expressing mutant Gab2 lacking the motif. Furthermore, T cells from Gab2-deficient mice showed enhanced proliferative responses upon TCR stimulation. These results indicate that Gads/Grb2-mediated LAT association is critical for the inhibitory function of Gab2, implying that Gab2 induced in stimulated T cells may exert an efficient negative feedback loop by recruiting inhibitory molecules to the lipid raft and competing with SLP-76 through Gads binding.

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