Document Detail

Sequential phosphorylation of SLP-76 at tyrosine 173 is required for activation of T and mast cells.
MedLine Citation:
PMID:  21725281     Owner:  NLM     Status:  MEDLINE    
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-γ1 (PLC-γ1) 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-γ1.
Meirav Sela; Yaron Bogin; Dvora Beach; Thomas Oellerich; Johanna Lehne; Jennifer E Smith-Garvin; Mariko Okumura; Elina Starosvetsky; Rachelle Kosoff; Evgeny Libman; Gary Koretzky; Taku Kambayashi; Henning Urlaub; Jürgen Wienands; Jonathan Chernoff; Deborah Yablonski
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-07-01
Journal Detail:
Title:  The EMBO journal     Volume:  30     ISSN:  1460-2075     ISO Abbreviation:  EMBO J.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-03     Completed Date:  2011-10-03     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  8208664     Medline TA:  EMBO J     Country:  England    
Other Details:
Languages:  eng     Pagination:  3160-72     Citation Subset:  IM    
Rappaport Family Institute for Research in the Medical Sciences, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
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MeSH Terms
Adaptor Proteins, Signal Transducing / metabolism*
Cells, Cultured
Interleukin-2 / secretion
Interleukin-6 / secretion
Lymphocyte Activation*
Mast Cells / immunology*
Phospholipase C gamma / metabolism
Phosphoproteins / metabolism*
Protein-Tyrosine Kinases / metabolism*
Signal Transduction*
T-Lymphocytes / immunology*
Tyrosine / metabolism
ZAP-70 Protein-Tyrosine Kinase / metabolism*
Grant Support
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Interleukin-2; 0/Interleukin-6; 0/Phosphoproteins; 0/SLP-76 signal Transducing adaptor proteins; 55520-40-6/Tyrosine; EC Kinases; EC Protein-Tyrosine Kinase; EC protein-tyrosine kinase; EC C gamma

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