Interaction of CD163 with the regulatory subunit of casein kinase II (CKII) and dependence of CD163 signaling on CKII and protein kinase C.
CD163 is a recently identified member of the scavenger receptor cysteine-rich superfamily, which is expressed on peripheral blood monocytes and most tissue macrophages and is thought to play an important role in the regulation of the inflammatory response of these cells. Cross-linking of CD163 on glucocorticoid-stimulated macrophages results in the secretion of several proinflammatory cytokines, but the precise mechanism of CD163 mediated signal transduction is not understood. The existence of several CD163 isoforms, which differ in the structure of their cytoplasmic domains and putative phosphorylation sites, suggests that these isoforms also differ in their signaling mechanism. Using the Yeast Two-Hybrid system and further in vitro and in vivo studies, we identified the regulatory beta-subunit of casein kinase II (CKII), which specifically binds to the cytoplasmic domain of CD163 and its isoforms. We also found, that in vitro the CD163 isoforms differ in their association with the CKII holoenzyme and in the phosphorylation by CKII. Furthermore, we demonstrated that the cytoplasmic domains of CD163 variants are phosphorylated by PKC-alpha in vitro. Inhibition studies using specific kinase inhibitors reveal that both CKII and PKC are involved in the CD163 signaling mechanism resulting in the secretion of proinflammatory cytokines.
Ritter
M
M
Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany.
Buechler
C
C
Kapinsky
M
M
Schmitz
G
G
D019794:2,3-Diphosphoglycerate / Q000494:pharmacology; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047390:Casein Kinase II; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D020035:Holoenzymes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D020798:Two-Hybrid System Techniques; D000098902:CD163 Antigen
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D020035:Holoenzymes; D007211:Indoles; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D008301:Maleimides; D020033:Protein Isoforms; D021122:Protein Subunits; D011956:Receptors, Cell Surface; D019794:2,3-Diphosphoglycerate; D004004:Dichlororibofuranosylbenzimidazole; D003907:Dexamethasone; D019833:Genistein; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; C088060:bisindolylmaleimide