Protein kinase C regulates expression and function of inhibitory killer cell Ig-like receptors in NK cells.
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.
Alvarez-Arias
Diana A
DA
Division of Basic Science, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Campbell
Kerry S
KS
D019943:Amino Acid Substitution / Q000235:genetics; D047390:Casein Kinase II / Q000502:physiology; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D054340:Receptors, KIR / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D054341:Receptors, KIR3DL1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013379:Substrate Specificity / Q000235:genetics; D013912:Threonine / Q000378:metabolism
D054340:Receptors, KIR; D054341:Receptors, KIR3DL1; D013912:Threonine; D018698:Glutamic Acid; D012694:Serine; D047390:Casein Kinase II; D011493:Protein Kinase C