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

Randy Shen,^1,2 Ying-Bin Ouyang,^2, Cheng-Kui Qu,^2, Andres Alonso,³ Lindsey Sperzel,³ Tomas Mustelin,³ Mark H. Kaplan,^2,4 and Gen-Sheng Feng^3*

Program in Signal Transduction Research, The Burnham Institute, La Jolla, California 92037,³ Departments of Biochemistry and Molecular Biologyof,¹ Microbiology and Immunology,⁴ Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202²

Received 28 November 2001/ Returned for modification 24 January 2002/ Accepted 21 February 2002

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.

Present address: Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.

Present address: American Red Cross, Rockville, MD 20855.

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