First Author | Sela M | Year | 2011 |
Journal | EMBO J | Volume | 30 |
Issue | 15 | Pages | 3160-72 |
PubMed ID | 21725281 | Mgi Jnum | J:175902 |
Mgi Id | MGI:5287915 | Doi | 10.1038/emboj.2011.213 |
Citation | Sela M, et al. (2011) Sequential phosphorylation of SLP-76 at tyrosine 173 is required for activation of T and mast cells. EMBO J 30(15):3160-72 |
abstractText | Cooperatively assembled signalling complexes, nucleated by adaptor proteins, integrate information from surface receptors to determine cellular outcomes. In T and mast cells, antigen receptor signalling is nucleated by three adaptors: SLP-76, Gads and LAT. Three well-characterized SLP-76 tyrosine phosphorylation sites recruit key components, including a Tec-family tyrosine kinase, Itk. We identified a fourth, evolutionarily conserved SLP-76 phosphorylation site, Y173, which was phosphorylated upon T-cell receptor stimulation in primary murine and Jurkat T cells. Y173 was required for antigen receptor-induced phosphorylation of phospholipase C-gamma1 (PLC-gamma1) in both T and mast cells, and for consequent downstream events, including activation of the IL-2 promoter in T cells, and degranulation and IL-6 production in mast cells. In intact cells, Y173 phosphorylation depended on three, ZAP-70-targeted tyrosines at the N-terminus of SLP-76 that recruit and activate Itk, a kinase that selectively phosphorylated Y173 in vitro. These data suggest a sequential mechanism whereby ZAP-70-dependent priming of SLP-76 at three N-terminal sites triggers reciprocal regulatory interactions between Itk and SLP-76, which are ultimately required to couple active Itk to its substrate, PLC-gamma1. |