Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function

Juliane Bubeck Wardenburg, Chong Fu, Janet K. Jackman, Horst Flotow, Sandra E. Wilkinson, David H. Williams, Robin Johnson, Guanghui Kong, Andrew C. Chan, Paul R. Findel

Research output: Contribution to journalArticle

254 Scopus citations

Abstract

Two families of tyrosine kinases, the Src and Syk families, are required for T-cell receptor activation. While the Src kinases are responsible for phosphorylation of receptor-encoded signaling motifs and for up-regulation of ZAP-70 activity, the downstream substrates of ZAP-70 are unknown. Evidence is presented herein that the Src homology 2 (SH2) domain-containing leukocyte protein of 76 kDa (SLP-76) is a substrate of ZAP-70. Phosphorylation of SLP- 76 is diminished in T cells that express a catalytically inactive ZAP-70. Moreover, SLP-76 is preferentially phosphorylated by ZAP-70 in vitro and in heterologous cellular systems. In T cells, overexpression of wild-type SLP-76 results in a hyperactive receptor, while expression of a SLP-76 molecule that is unable to be tyrosine-phosphorylated attenuates receptor function. In addition, the SH2 domain of SLP-76 is required for T-cell receptor function, although its role is independent of the ability of SLP-76 to undergo tyrosine phosphorylation. As SLP-76 interacts with both Grb2 and phospholipase C-γ1, these data indicate that phosphorylation of SLP-76 by ZAP-70 provides an important functional link between the T-cell receptor and activation of ras and calcium pathways.

Original languageEnglish
Pages (from-to)19641-19644
Number of pages4
JournalJournal of Biological Chemistry
Volume271
Issue number33
DOIs
StatePublished - Sep 5 1996
Externally publishedYes

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    Wardenburg, J. B., Fu, C., Jackman, J. K., Flotow, H., Wilkinson, S. E., Williams, D. H., Johnson, R., Kong, G., Chan, A. C., & Findel, P. R. (1996). Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. Journal of Biological Chemistry, 271(33), 19641-19644. https://doi.org/10.1074/jbc.271.33.19641