Protein kinase C regulates expression and function of inhibitory killer cell ig-like receptors in NK cells
Protein kinase C regulates expression and function of inhibitory killer cell ig-like receptors in NK cells
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DOI：
10.4049/jimmunol.179.8.5281
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发表时间：
2007-10-15
影响因子：
4.4
通讯作者：
Campbell, Kerry S.
中科院分区：
文献类型：
--
作者：
Alvarez-Arias, Diana A.;Campbell, Kerry S.
抑制性杀伤细胞免疫球蛋白样受体(KIR)通过与正常细胞表达的MHC-I类分子结合，激活含有Src同源2结构域的蛋白酪氨酸磷酸酶1和2，从而负向调节NK细胞的细胞毒作用。这需要胞浆区ITIMs上KIR的酪氨酸磷酸化。令人惊讶的是，我们发现KIR3DL1在丝氨酸上有强烈的结构性磷酸化，在苏氨酸残基上有微弱的磷酸化。在这项研究中，我们在KIR细胞质结构域上定位了酪蛋白激酶、蛋白激酶C和一个未知的激酶的组成磷酸化位点。其中三个磷酸化位点在人类抑制性KIR中高度保守。对野生型受体和丝氨酸/苏氨酸突变体的功能研究表明，蛋白激酶C对Ser(394)的磷酸化略微抑制KIR3DL1的抑制功能，并减少受体的内化和周转。我们的结果提供了丝氨酸/苏氨酸磷酸化是KIR功能的重要调节机制的证据。
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.