Sequential involvement of Lck and SHP-1 with MHC-recognizing receptors on NK cells inhibits FcR-initiated tyrosine kinase activation

Bryce A. Binstadt, Kathryn M. Brumbaugh, Christopher J. Dick, Andrew M. Scharenberg, Brandi L. Williams, Marco Colonna, Lewis L. Lanier, Jean Pierre Kinet, Robert T. Abraham, Paul J. Leibson

Research output: Contribution to journalArticlepeer-review

245 Scopus citations

Abstract

Recognition of major histocompatibility (MHC) class I complexes on target cells by killer cell inhibitory receptors (KIR) blocks natural killer (NK) and T cell cytotoxic function. The inhibitory effect of KIR ligation requires the phosphotyrosine-dependent association of KIR with the cytoplasmic SH2-containing protein tyrosine phosphatase SHP-1. Using a somatic genetic model, we first define a requirement for the Src family protein tyrosine kinase (PTK) Lck in mediating KIR tyrosine phosphorylation. We then investigate how KIR ligation interrupts PTK-dependent NK cell activation signals. Specifically, we show that KIR ligation inhibits the Fc receptor (FcR)-induced tyrosine phosphorylation of the FcR-associated ζ signaling chain, the PTK ZAP-70, and phospholipase Cγ. Overexpression of catalytically inactive SHP-1 (acting as a dominant negative) restores the tyrosine phosphorylation of these signaling events and reverses KIR-mediated inhibition of NK cell cytotoxic function. These results suggest sequential roles for Lck and SHP-1 in the inhibition of PTK following MHC recognition by NK cells.

Original languageEnglish (US)
Pages (from-to)629-638
Number of pages10
JournalImmunity
Volume5
Issue number6
DOIs
StatePublished - Dec 1996

Bibliographical note

Funding Information:
Correspondence should be addressed to P. J. L. This research was supported by the Mayo Foundation and by National Institutes of Health grants CA47752 and GM47286.

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