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Molecular and Cellular Biology, July 2001, p. 4208-4218, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4208-4218.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Identification of a Phospholipase C-gamma 1 (PLC-gamma 1) SH3 Domain-Binding Site in SLP-76 Required for T-Cell Receptor-Mediated Activation of PLC-gamma 1 and NFAT

Deborah Yablonski,1 Theresa Kadlecek,2 and Arthur Weiss2,*

Department of Pharmacology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Bat Galim, Haifa 31096, Israel,1 and Department of Medicine, Department of Microbiology and Immunology, and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California 94143-07952

Received 9 October 2000/Returned for modification 14 December 2000/Accepted 4 April 2001

SLP-76 is an adapter protein required for T-cell receptor (TCR) signaling. In particular, TCR-induced tyrosine phosphorylation and activation of phospholipase C-gamma 1 (PLC-gamma 1), and the resultant TCR-inducible gene expression, depend on SLP-76. Nonetheless, the mechanisms by which SLP-76 mediates PLC-gamma 1 activation are not well understood. We now demonstrate that SLP-76 directly interacts with the Src homology 3 (SH3) domain of PLC-gamma 1. Structure-function analysis of SLP-76 revealed that each of the previously defined protein-protein interaction domains can be individually deleted without completely disrupting SLP-76 function. Additional deletion mutations revealed a new, 67-amino-acid functional domain within the proline-rich region of SLP-76, which we have termed the P-1 domain. The P-1 domain mediates a constitutive interaction of SLP-76 with the SH3 domain of PLC-gamma 1 and is required for TCR-mediated activation of Erk, PLC-gamma 1, and NFAT (nuclear factor of activated T cells). The adjacent Gads-binding domain of SLP-76, also within the proline-rich region, mediates inducible recruitment of SLP-76 to a PLC-gamma 1-containing complex via the recruitment of both PLC-gamma 1 and Gads to another cell-type-specific adapter, LAT. Thus, TCR-induced activation of PLC-gamma 1 entails the binding of PLC-gamma 1 to both LAT and SLP-76, a finding that may underlie the requirement for both LAT and SLP-76 to mediate the optimal activation of PLC-gamma 1.

* Corresponding author. Mailing address: Department of Medicine, Department of Microbiology and Immunology, and Howard Hughes Medical Institute, U426, Box 0795, University of California, San Francisco, 533 Parnassus Ave., San Francisco, CA 94143-0795. Phone: (415) 476-1291. Fax: (415) 502-5081. E-mail: aweiss{at}medicine.ucsf.edu.

Molecular and Cellular Biology, July 2001, p. 4208-4218, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4208-4218.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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