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Sequential phosphorylation of SLP‐76 at tyrosine 173 is required for activation of T and mast cells
Author(s) -
Sela Meirav,
Bogin Yaron,
Beach Dvora,
Oellerich Thomas,
Lehne Johanna,
SmithGarvin Jennifer E,
Okumura Mariko,
Starosvetsky Elina,
Kosoff Rachelle,
Libman Evgeny,
Koretzky Gary,
Kambayashi Taku,
Urlaub Henning,
Wienands Jürgen,
Chernoff Jonathan,
Yablonski Deborah
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.213
Subject(s) - biology , phosphorylation , mast (botany) , tyrosine , tyrosine phosphorylation , microbiology and biotechnology , mast cell , biochemistry , immunology
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‐ γ 1 (PLC‐ γ 1) 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‐ γ 1.