Grap Negatively Regulates T-Cell Receptor-Elicited Lymphocyte Proliferation and Interleukin-2 Induction

Abstract

Grb-2-related adaptor protein (Grap) is a Grb2-like SH3-SH2-SH3 adaptor protein with expression restricted to lymphoid tissues. Grap^−/− lymphocytes isolated from targeted Grap-deficient mice exhibited enhanced proliferation, interleukin-2 production, and c-fos induction in response to mitogenic T-cell receptor (TCR) stimulation, compared to wild-type cells. Ectopic expression of Grap led to a suppression of Elk-1-directed transcription induced by the Ras/Erk pathway, without having effects on gene expression mediated by Jnk and p38 mitogen-activated protein kinases. Together, these data suggest that Grap, unlike Grb2, acts as a negative regulator of TCR-stimulated intracellular signaling by downregulating signal relay through the Ras/Erk pathway.

We thank G. A. Koretzky, K.-L. Guan, M. Marshall, B. Mayer, and L. Quilliam for expression vectors and thank X. Lu, K. Pearle, and S. Reid for technical assistance.

This work was supported by grants from the American Cancer Society (RPG-98-273-01-TBE) and National Institutes of Health (HL66208) to G.-S.F., (AI45515) to M.H.K., and (AI40552) to T.M.