LCK phosphorylated human killer cell inhibitory receptors recruit and activate phosphatidylinositol 3-kinase

F. Marti, C. W. Xu, A. Selvakumar, R. Brent, B. Dupont, P. D. King

Research output: Contribution to journalArticlepeer-review

Abstract

HLA-specific killer cell inhibitory receptors (KIR) impede NK and T cell activation programs through recruitment of the SH2 domain-containing tyrosine phosphatases, SHP-1 and SHP-2, to their cytoplasmic tails (CYT). To identify additional KIR-binding SH2 domain-containing proteins we used the p58 CL6 KIR CYT as a bait in the recently described yeast two-bait interaction trap and a modified version of this system both of which permit tyrosine phosphorylation of bait proteins consequent to the introduction into yeast of protein tyrosine kinases. Using these systems, we report that CL6 CYT, once phosphorylated by the src-family tyrosine kinase, LCK, specifically bound not only SHP-2 but also the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K) from a library of potential interactors. Similarly, other KIR CYT, although not all types of tail, were found to bind p85α in yeast following phosphorylation of KIR by LCK. Mutational analysis of the CL6 CYT revealed that, like SHP-1 and SHP-2, p85α is recruited to the most membrane proximal of two ITIMs. In the NK cell line, NK3.3, cross-linking of KIR resulted in the recruitment of p85α to KIR CYT as well as an increase in the lipid kinase activity of PI3K. These results, therefore, suggest, that in addition to providing negative signals, KIR may also contribute positive signals for NK and T cell growth and/or survival.

Original languageEnglish
Pages (from-to)A903
JournalFASEB Journal
Volume12
Issue number5
StatePublished - Mar 20 1998

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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