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© The Rockefeller University Press, 0022-1007/2000/2/463/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 3, February 7, 2000 463-474

Original Article

Src-like Adaptor Protein (Slap) Is a Negative Regulator of T Cell Receptor Signaling

Tomasz Sosinowskia, Akhilesh Pandeyd,e, Vishva M. Dixitf, and Arthur Weissa,b,c

a Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, California 94143-0795
b Department of Medicine, University of California at San Francisco, San Francisco, California 94143-0795
c Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 94143-0795
d Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115
e Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142
f Genentech, Inc., South San Francisco, California 94080
Department of Medicine, Howard Hughes Medical Institute, University of California at San Francisco, 533 Parnassas Ave., U-330, San Francisco, CA 94143-0795.415-502-5081415-476-1291

aweiss{at}medicine.ucsf.edu

Initiation of T cell antigen receptor (TCR) signaling is dependent on Lck, a Src family kinase. The Src-like adaptor protein (SLAP) contains Src homology (SH)3 and SH2 domains, which are highly homologous to those of Lck and other Src family members. Because of the structural similarity between Lck and SLAP, we studied its potential role in TCR signaling. Here, we show that SLAP is expressed in T cells, and that when expressed in Jurkat T cells it can specifically inhibit TCR signaling leading to nuclear factor of activated T cells (NFAT)-, activator protein 1 (AP-1)–, and interleukin 2–dependent transcription. The SH3 and SH2 domains of SLAP are required for maximal attenuation of TCR signaling. This inhibitory activity can be bypassed by the combination of phorbol myristate acetate (PMA) and ionomycin, suggesting that SLAP acts proximally in the TCR signaling pathway. SLAP colocalizes with endosomes in Jurkat and in HeLa cells, and is insoluble in mild detergents. In stimulated Jurkat cells, SLAP associates with a molecular signaling complex containing CD3{zeta}, ZAP-70, SH2 domain–containing leukocyte protein of 76 kD (SLP-76), Vav, and possibly linker for activation of T cells (LAT). These results suggest that SLAP is a negative regulator of TCR signaling.

Key Words: Lck • Src homology 2 • T cell activation • calcium flux • endosomes

Abbreviations used in this paper: AP-1, activator protein 1; CI-M6PR, cation-independent mannose 6-phosphate receptor; FLAG, fluoresceinated antigen; GST, glutathione S-transferase; HRP, horseradish peroxidase; IP, immunoprecipitation; ITAM, immunoreceptor tyrosine-based activation motif; LAT, linker for activation of T cells; NFAT, nuclear factor of activated T cells; PDGFR, platelet-derived growth factor receptor; PTyr, phosphotyrosine; SH, Src homology; SLAP, Src-like adaptor protein; SLP-76, SH2 domain–containing leukocyte protein of 76 kD; TAg, large T antigen; WCL, whole cell lysate; WT, wild-type.

© 2000 The Rockefeller University Press


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