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

• Published in: Journal of Immunology Vol. 179; no. 8; pp. 5281 - 5290
• Main Authors: Alvarez-Arias, Diana A, Campbell, Kerry S
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.10.2007
• Subjects: Amino Acid Substitution - genetics; Casein Kinase II - physiology; Cell Line; Cell Line, Transformed; Cell Line, Tumor; Cytotoxicity, Immunologic - genetics; Down-Regulation - genetics; Down-Regulation - immunology; Glutamic Acid - chemistry; Glutamic Acid - metabolism; Humans; Killer Cells, Natural - enzymology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Phosphorylation; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - physiology; Receptors, KIR - antagonists & inhibitors; Receptors, KIR - biosynthesis; Receptors, KIR - genetics; Receptors, KIR - physiology; Receptors, KIR3DL1 - antagonists & inhibitors; Receptors, KIR3DL1 - genetics; Receptors, KIR3DL1 - metabolism; Serine - metabolism; Substrate Specificity - genetics; Threonine - metabolism
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.179.8.5281

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 Ser(394) 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.