The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/5/1383/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 9, May 3, 1999 1383-1390

Articles

Grf40, A Novel Grb2 Family Member, Is Involved in T Cell Signaling through Interaction with SLP-76 and LAT

Hiroshi Asada*,{ddagger}, Naoto Ishii*, Yoshiteru Sasaki*, Kazuhiro Endo*, Hirotake Kasai*, Nobuyuki Tanaka*, Toshikazu Takeshita*, Shigeru Tsuchiya{ddagger}, Tasuke Konno§, and Kazuo Sugamura*,||

From the * Department of Microbiology and Immunology, Tohoku University School of Medicine, Sendai 980-8575, Japan; the {ddagger} Department of Pediatric Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; the § Research Institute, Miyagi Cancer Center, Natori 981-1293, Japan; and || Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Tokyo 101-0062, Japan

We molecularly cloned a new Grb2 family member, named Grf40, containing the common SH3-SH2-SH3 motif. Expression of Grf40 is predominant in hematopoietic cells, particularly T cells. Grf40 binds to the SH2 domain–containing leukocyte protein of 76 kD (SLP-76) via its SH3 domain more tightly than Grb2. Incidentally, Grf40 binds to linker for activation of T cells (LAT) possibly via its SH2 domain. Overexpression of wild-type Grf40 in Jurkat cells induced a significant increase of SLP-76–dependent interleukin (IL)-2 promoter and nuclear factor of activated T cell (NF-AT) activation upon T cell receptor (TCR) stimulation, whereas the COOH-terminal SH3-deleted Grf40 mutant lacked any recognizable increase in IL-2 promoter activity. Furthermore, the SH2-deleted Grf40 mutant led to a marked inhibition of these regulatory activities, the effect of which is apparently stronger than that of the SH2-deleted Grb2 mutant. Our data suggest that Grf40 is an adaptor molecule involved in TCR-mediated signaling through a more efficient interaction than Grb2 with SLP-76 and LAT.

Key Words: Grb2 family • SLP-76 • T cell receptor signaling • nuclear factor of activated T cells

Address correspondence to Kazuo Sugamura, Department of Microbiology and Immunology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Phone: 81-22-717-8096; Fax: 81-22-717-8097; E-mail: sugamura{at}mail.cc.tohoku.ac.jp

Abbreviations used: LAT, linker for activation of T cells; NF-AT, nuclear factor of activated T cells; PTK, protein tyrosine kinase; SLP-76, SH2 domain–containing leukocyte protein of 76 kD; STAM, signal transducing adaptor molecule.


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