Journal of Leukocyte Biology
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1206736

Received for publication December 19, 2006.
Revised May 21, 2007.
Accepted for publication May 22, 2007.

Article

Rapid T cell receptor-mediated SHP-1 S591 phosphorylation regulates SHP-1 cellular localization and phosphatase activity

Yin Liu , Michael J. Kruhlak , Jian-Jiang Hao , and Stephen Shaw @

Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

@ To whom correspondence should be addressed. E-mail: sshaw{at}nih.gov.


  Abstract

Since the tyrosine phosphatase SHP-1 plays a major role in regulating T cell signaling, we investigated regulation thereof by Ser/Thr phosphorylation. We found that T cell receptor (TCR) stimulation induced fast (≤1 min) and transient phosphorylation of SHP-1 S591 in both Jurkat and human peripheral blood T-cells (PBT). Phosphorylation of S591 in T-cells could be mediated artificially by a constitutive active PKC-theta construct, but the dose dependence of inhibition by PKC inhibitors indicated that PKCs were not the relevant basophilic kinase in the physiological response. S591 phosphorylation inhibited phosphatase function since a S591D mutant had lower activity than the S591A mutant. Additional evidence that S591 phosphorylation alters SHP-1 function was provided by studies of Jurkat cells stably expressing SHP-1 wild type or mutants. In those cells, S591D mutation reduced the capacity of transfected SHP-1 to inhibit TCR-induced phosphorylation of PLC-{gamma}1. Interestingly, SHP-1 Y536 phosphorylation (previously shown to augment phosphatase activity) was also induced in PBT by TCR signal but at a much later time compared with S591 (~30 min). S591 phosphorylation also altered cellular distribution of SHP-1 because: 1) SHP-1 in lipid rafts and a sheared membrane fraction was hypophosphorylated; 2) In stably transfected Jurkat cell lines, S591D mutant protein had reduced presence in both lipid raft and the sheared membrane fraction; 3) S591 phosphorylation prevented nuclear localization of a C-terminal GFP tagged SHP-1 construct. Our studies also shed light on an additional mechanism regulating SHP-1 nuclear localization, namely conformational autoinhibition. These findings highlight elegant regulation of SHP-1 by sequential phosphorylation of serine then tyrosine.

Key Words: T lymphocyte • signal transduction • lipid raft • nuclear localization




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