NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells

Jadee L. Upshaw, Laura N. Arneson, Renee A. Schoon, Christopher J. Dick, Daniel D. Billadeau, Paul J. Leibson

Research output: Contribution to journalArticlepeer-review

174 Scopus citations

Abstract

NKG2D is an important immunosurveillance receptor that responds to stress-induced ligand expression on tumors and virus-infected cells. Human natural killer cells express NKG2D and require the transmembrane adaptor DAP10 to initiate their full cytotoxic activation. However, DAP10 has no immunoreceptor tyrosine-based activation motif and thus the mechanism of recruiting 'downstream' effector proteins is unclear. We show here that binding of the p85 subunit of phosphatidylinositol-3- kinase to DAP10 could not by itself trigger cell-mediated cytotoxicity and that binding of an intermediate consisting of the DAP10 binding partner Grb2 and the effector molecule Vav1 (Grb2-Vav1) to DAP10 was sufficient to initiate tyrosine-phosphorylation events. For full calcium release and cytotoxicity to occur, both Grb2-Vav1 and p85 had to bind to DAP10. These findings identify a previously unknown mechanism by which NKG2D-DAP10 mediates cytotoxicity and provides a framework for evaluating activation by other receptor complexes that lack immunoreceptor tyrosine-based activation motifs.

Original languageEnglish (US)
Pages (from-to)524-532
Number of pages9
JournalNature immunology
Volume7
Issue number5
DOIs
StatePublished - May 1 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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