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J. Biol. Chem., Vol. 277, Issue 15, 13331-13337, April 12, 2002
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From the Department of Pathology and Laboratory Medicine, British
Columbia's Children's Hospital and University of British Columbia,
4480 Oak Street, Vancouver, British Columbia V6H 3V4, Canada
Natural killer (NK) cells express an
activating receptor, 2B4, that enhances cellular cytotoxicity. Upon NK
cell activation by ligation of 2B4, the intracellular domain of 2B4
associates with the X-linked lymphoproliferative disease (XLP) gene
product, signaling lymphocytic activation molecule-associated
protein/SH2D1A (SAP/SH2D1A). Defective intracellular association of 2B4
with mutated SAP/SH2D1A is likely to underlie the defects in
cytotoxicity observed in NK cells from patients with XLP. We report
here a role for phosphoinositide 3-kinase (PI3K) in the recruitment
and association of SAP/SH2D1A to 2B4 in human NK cells. The activation of normal NK cells by ligation of 2B4 leads to the phosphorylation of
2B4, recruitment of SAP/SH2D1A, and association of the p85 regulatory
subunit of PI3K. The inhibition of PI3K enzymatic activity with either
wortmannin or LY294002 prior to 2B4 ligation does not alter the
association of 2B4 with the p85 subunit but prevents the recruitment of
SAP/SH2D1A to 2B4. In addition, PI3K inhibitors significantly diminish
the cytotoxic function of primary NK cells. This observed inhibition of
cytotoxicity, present in normal NK cells, was less apparent or absent
in NK cells derived from a patient with XLP. These data indicate that
the cytotoxicity of activated NK cells is mediated by the association
of 2B4 and SAP/SH2D1A, and that this association is dependent upon the
activity of PI3K.
This paper is dedicated to the Kaska people of northwestern Canada.
Association of the X-linked Lymphoproliferative Disease Gene
Product SAP/SH2D1A with 2B4, a Natural Killer Cell-activating Molecule,
Is Dependent on Phosphoinositide 3-Kinase*
and
*
This work was supported by the Canadian Institutes of Health
Research and the British Columbia's Children's Hospital Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by the Michael Smith Foundation for Health Research.
§
To whom correspondence should be addressed: Dept. of Pathology & Laboratory Medicine, BC's Children's Hospital, 4480 Oak St., Rm. 2G5,
Vancouver, BC V6H 3V4, Canada. Tel.: 604-875-3605; Fax: 604-875-3777;
E-mail: roo@interchange.ubc.ca.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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