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Mol. Cell. Biol. doi:10.1128/MCB.01477-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

PI3-kinase activation is required to form the NKG2D immunological synapse

Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Experimental Immunology, Institute of Development, Aging 9and Cancer, Tohoku University, Seiryo 4-1, Sendai 980-8575, Japan; RIKEN Research Center for Allergy and Immunology, Laboratory for Lymphocyte Differentiation, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; Departments of Medicine, Cell Biology, Washington University, St Louis, MO 63110, USA

^* To whom correspondence should be addressed. Email: shaw{at}pathology.wustl.edu.

	Abstract

The receptor NKG2D allows natural killer (NK) cells to detect virally infected, stressed and tumor cells. In human cells, NKG2D signaling is mediated through the associated DAP10 adaptor. Here we show that engagement of NKG2D by itself is sufficient to stimulate the formation of the NK immunological synapse (NKIS) with recruitment of NKG2D to the center synapse. Mutagenesis studies of DAP10 revealed that the PI3-kinase but not the Grb2 binding site of DAP10 was required and sufficient for recruitment of DAP10 into the NKIS. Surprisingly, we found that in the absence of the Grb2 binding site, Grb2 was still recruited into the NKIS. As the recruitment of Grb2 was dependent on PIP₃, we explored the possibility that recruitment to the NKIS is mediated by a PH-domain containing binding partner for Grb2. We found that the PH domain of SOS1 but not Vav1 was able to be recruited by PIP₃. These results provide new insights into the mechanism of immunological synapse formation and also demonstrate how multiple mechanisms can be used to recruit the same signaling proteins to the plasma membrane.