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.
1 (PLC-
1)
SH3 Domain-Binding Site in SLP-76 Required for T-Cell Receptor-Mediated
Activation of PLC-
1 and NFAT
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-
1 (PLC-
1), and the resultant TCR-inducible gene expression, depend on SLP-76. Nonetheless, the
mechanisms by which SLP-76 mediates PLC-
1 activation are not well
understood. We now demonstrate that SLP-76 directly interacts with the
Src homology 3 (SH3) domain of PLC-
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-
1 and
is required for TCR-mediated activation of Erk, PLC-
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-
1-containing complex via the
recruitment of both PLC-
1 and Gads to another cell-type-specific
adapter, LAT. Thus, TCR-induced activation of PLC-
1 entails the
binding of PLC-
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-
1.
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