Protein kinase C regulates expression and function of inhibitory killer cell Ig-like receptors in NK cells

Diana A. Alvarez-Arias, Kerry S. Campbell

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)5281-5290
Number of pages10
JournalJournal of Immunology
Volume179
Issue number8
DOIs
StatePublished - Oct 15 2007

Keywords

  • Amino Acid Substitution/genetics
  • Casein Kinase II/physiology
  • Cell Line
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic/genetics
  • Down-Regulation/genetics
  • Glutamic Acid/chemistry
  • Humans
  • Killer Cells, Natural/enzymology
  • Phosphorylation
  • Protein Kinase C/antagonists & inhibitors
  • Receptors, KIR/antagonists & inhibitors
  • Receptors, KIR3DL1/antagonists & inhibitors
  • Serine/metabolism
  • Substrate Specificity/genetics
  • Threonine/metabolism

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