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Protein Kinase C Regulates Expression and Function of Inhibitory Killer Cell Ig-Like Receptors in NK Cells¹

Division of Basic Science, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111

The inhibitory killer cell Ig-like receptors (KIR) negatively regulate NK cell cytotoxicity by activating the Src homology 2 domain-containing protein tyrosine phosphatases 1 and 2 following ligation with MHC class I molecules expressed on normal cells. This requires tyrosine phosphorylation of KIR on ITIMs in the cytoplasmic domain. Surprisingly, we have found that KIR3DL1 is strongly and constitutively phosphorylated on serine and weakly on threonine residues. In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase C, and an unidentified kinase on the KIR cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory KIR. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser³⁹⁴ by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover. Our results provide evidence that serine/threonine phosphorylation is an important regulatory mechanism of KIR function.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant CA083859 (to K.S.C.) and Training Grant CA09035-30 (to D.A.A.) from the National Institutes of Health. The research was also supported in part by National Institutes of Health CORE Grant CA06927 and an appropriation from the Commonwealth of Pennsylvania. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

² Address correspondence and reprint requests to Dr. Kerry S. Campbell, Division of Basic Science, Fox Chase Cancer Center, Institute for Cancer Research, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail address: kerry.campbell{at}fccc.edu

³ Abbreviations used in this paper: MHC-I, class I MHC; KIR, killer cell Ig-like receptor; CK, casein kinase; PKC, protein kinase C; WT, wild-type; SHP, Src homology 2 domain-containing protein tyrosine phosphatase; PVDF, polyvinylidene difluoride; MFI, mean fluorescence intensity.