SHP-1 regulates Lck-induced phosphatidylinositol 3-kinase phosphorylation and activity

Bruce Cuevas, Yiling Lu, Steven Watt, Rakesh Kumar, Jinyi Zhang, Katherine A. Siminovitch, Gordon Mills

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

Ligation of the T cell antigen receptor (TCR) activates the Src family tyrosine kinase p56 Lck, which, in turn, phosphorylates a variety of intracellular substrates. The phosphatidylinositol 3-kinase (PI3K) and the tyrosine phosphatase SHP-1 are two Lck substrates that have been implicated in TCR signaling. In this study, we demonstrate that SHP-1 co- immunoprecipitates with the p85 regulatory subunit of PI3K in Jurkat T cells, and that this association is increased by ligation of the TCR complex. Co- expression of SHP-1 and PI3K with a constitutively activated form of Lck in COS7 cells demonstrated the carboxyl-terminal SH2 domain of PI3K to inducibly associate with the full-length SHP-1 protein. By contrast, a truncated SHP-1 mutant lacking the Lck phosphorylation site (Tyr564) failed to bind p85. Wild-type but not catalytically inactive SHP-1 induced dephosphorylation of p85. Furthermore, expression of SHP-1 decreased PI3K enzyme activity in anti- phosphotyrosine immunoprecipitates and phosphorylation of serine 473 in Akt, a process dependent on PI3K activity. These results indicate the presence of a functional interaction between PI3K and SHP-1 and suggest that PI3K signaling, which has been implicated in cell proliferation, apoptosis, cytoskeletal reorganization, and many other biological activities, can be regulated by SHP-1 in T lymphocytes.

Original languageEnglish (US)
Pages (from-to)27583-27589
Number of pages7
JournalJournal of Biological Chemistry
Volume274
Issue number39
DOIs
StatePublished - Sep 24 1999
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinase
Phosphorylation
T-Cell Antigen Receptor
T-cells
Ligation
Non-Receptor Type 6 Protein Tyrosine Phosphatase
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
T-Lymphocytes
Phosphotyrosine
Jurkat Cells
src Homology Domains
src-Family Kinases
Cell proliferation
Enzyme activity
Substrates
Bioactivity
Serine
Cell Proliferation
Association reactions
Apoptosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

SHP-1 regulates Lck-induced phosphatidylinositol 3-kinase phosphorylation and activity. / Cuevas, Bruce; Lu, Yiling; Watt, Steven; Kumar, Rakesh; Zhang, Jinyi; Siminovitch, Katherine A.; Mills, Gordon.

In: Journal of Biological Chemistry, Vol. 274, No. 39, 24.09.1999, p. 27583-27589.

Research output: Contribution to journalArticle

Cuevas, Bruce ; Lu, Yiling ; Watt, Steven ; Kumar, Rakesh ; Zhang, Jinyi ; Siminovitch, Katherine A. ; Mills, Gordon. / SHP-1 regulates Lck-induced phosphatidylinositol 3-kinase phosphorylation and activity. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 39. pp. 27583-27589.
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