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

Publication ,  Journal Article
Upshaw, JL; Arneson, LN; Schoon, RA; Dick, CJ; Billadeau, DD; Leibson, PJ
Published in: Nat Immunol
May 2006

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.

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Published In

Nat Immunol

DOI

ISSN

1529-2908

Publication Date

May 2006

Volume

7

Issue

5

Start / End Page

524 / 532

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptors, Natural Killer Cell
  • Receptors, Immunologic
  • Proto-Oncogene Proteins c-vav
  • Phosphorylation
  • Phosphatidylinositol 3-Kinases
  • NK Cell Lectin-Like Receptor Subfamily K
  • Models, Biological
  • Membrane Proteins
  • Killer Cells, Natural
 

Citation

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Upshaw, J. L., Arneson, L. N., Schoon, R. A., Dick, C. J., Billadeau, D. D., & Leibson, P. J. (2006). NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells. Nat Immunol, 7(5), 524–532. https://doi.org/10.1038/ni1325
Upshaw, Jadee L., Laura N. Arneson, Renee A. Schoon, Christopher J. Dick, Daniel D. Billadeau, and Paul J. Leibson. “NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells.Nat Immunol 7, no. 5 (May 2006): 524–32. https://doi.org/10.1038/ni1325.
Upshaw JL, Arneson LN, Schoon RA, Dick CJ, Billadeau DD, Leibson PJ. NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells. Nat Immunol. 2006 May;7(5):524–32.
Upshaw, Jadee L., et al. “NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells.Nat Immunol, vol. 7, no. 5, May 2006, pp. 524–32. Pubmed, doi:10.1038/ni1325.
Upshaw JL, Arneson LN, Schoon RA, Dick CJ, Billadeau DD, Leibson PJ. NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells. Nat Immunol. 2006 May;7(5):524–532.

Published In

Nat Immunol

DOI

ISSN

1529-2908

Publication Date

May 2006

Volume

7

Issue

5

Start / End Page

524 / 532

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptors, Natural Killer Cell
  • Receptors, Immunologic
  • Proto-Oncogene Proteins c-vav
  • Phosphorylation
  • Phosphatidylinositol 3-Kinases
  • NK Cell Lectin-Like Receptor Subfamily K
  • Models, Biological
  • Membrane Proteins
  • Killer Cells, Natural