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© The Rockefeller University Press, 0022-1007/1999/4/1243/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 8, April 19, 1999 1243-1253

Articles

GrpL, a Grb2-related Adaptor Protein, Interacts with SLP-76 to Regulate Nuclear Factor of Activated T Cell Activation

Che-Leung Law*, Maria K. Ewings*, Preet M. Chaudhary{ddagger}, Sasha A. Solow*, Theodore J. Yun*, Aaron J. Marshall*, Leroy Hood{ddagger}, and Edward A. Clark*,§

From the * Department of Microbiology, the {ddagger} Department of Molecular Biotechnology, and the § Regional Primate Research Center, University of Washington, Seattle, Washington 98195

Propagation of signals from the T cell antigen receptor (TCR) involves a number of adaptor molecules. SH2 domain–containing protein 76 (SLP-76) interacts with the guanine nucleotide exchange factor Vav to activate the nuclear factor of activated cells (NF-AT), and its expression is required for normal T cell development. We report the cloning and characterization of a novel Grb2-like adaptor molecule designated as Grb2-related protein of the lymphoid system (GrpL). Expression of GrpL is restricted to hematopoietic tissues, and it is distinguished from Grb2 by having a proline-rich region. GrpL can be coimmunoprecipitated with SLP-76 but not with Sos1 or Sos2 from Jurkat cell lysates. In contrast, Grb2 can be coimmunoprecipitated with Sos1 and Sos2 but not with SLP-76. Moreover, tyrosine-phosphorylated LAT/pp36/38 in detergent lysates prepared from anti-CD3 stimulated T cells associated with Grb2 but not GrpL. These data reveal the presence of distinct complexes involving GrpL and Grb2 in T cells. A functional role of the GrpL–SLP-76 complex is suggested by the ability of GrpL to act alone or in concert with SLP-76 to augment NF-AT activation in Jurkat T cells.

Key Words: GrpL • SLP-76 • Grb2 • nuclear factor of activated cells • cell activation

Address correspondence to Edward A. Clark, Department of Microbiology, Box 357242, University of Washington, Seattle, WA 98195. Phone: 206-543-8706; Fax: 206-685-0305; E-mail: eclark{at}bart.rprc.washington.edu

C.-L. Law's present address is Xcyte Therapies Inc., 2203 Airport Way South, Suite 300, Seattle, WA 98134.

C.-L. Law, M.K. Ewings, and P.M. Chaudhary all contributed equally to this study.

Abbreviations used: GEF, guanine nucleotide exchange factor; GrpL, Grb2-related protein of the lymphoid system; IP, immunoprecipitate; MAPK, mitogen-activated protein kinase; NF-AT, nuclear factor of activated T cells; PTK, protein tyrosine kinase; SH, src homology; SHP, SH2 domain–containing protein tyrosine phosphatase; SLP-76, SH2 domain–containing leukocyte protein of 76 kD.


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