期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 21, 期 13, 页码 4208-4218出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.21.13.4208-4218.2001
关键词
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资金
- NCI NIH HHS [R01 CA072531, CA72531] Funding Source: Medline
SLP-76 is an adapter protein required for T-cell receptor (TCR) signaling. In particular, TCR-induced tyrosine phosphorylation and activation of phospholipase C-gammal (PLC-gammal), and the resultant TCR-inducible gene expression, depend on SLP-76. Nonetheless, the mechanisms by which SLP-76 mediates PLC-gamma1 activation are not well understood. We now demonstrate that SLP-76 directly interacts with the Src homology 3 (SH3) domain of PLC-gammal. 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-gammal and is required for TCR-mediated activation of Erk, PLC-gammal, 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-gammal-containing complex via the recruitment of both PLC-gammal and Gads to another cell-type-specific adapter, LAT. Thus, TCR-induced activation of PLC-gammal entails the binding of PLC-gammal 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-gammal.
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