Protein kinase C activity is rate limiting for shedding of the interleukin-6 receptor.
An analysis of the mechanism of generation of the soluble interleukin-6 receptor (IL-6R) has been performed. The membrane-bound receptor is proteolytically cleaved to release a soluble receptor form which retained its ligand binding capacity. Furthermore, the soluble IL-6R is unique in its ability to induce a biological signal in complex with the ligand interleukin-6 (IL-6) on cells which by themselves do not bind IL-6. Shedding of the IL-6R is strongly activated by PMA and can be inhibited by the protein kinase inhibitor staurosporine. The generation of the IL-6R is not dependent on protein synthesis. The inactive PMA analogue 4-alpha-phorbol-12,13-didecanoate fails to induce shedding of the IL-6R. Transfection of a protein kinase C expression plasmid into IL-6R expressing cells leads to enhanced shedding of the receptor. These experiments clearly show that protein kinase C regulates shedding of the IL-6R.
Müllberg
J
J
Institut für Biochemie, RWTH Aachen, Germany.
Schooltink
H
H
Stoyan
T
T
Heinrich
P C
PC
Rose-John
S
S
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007700:Kinetics; D008113:Liver Neoplasms; D046911:Macromolecular Substances; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019311:Staurosporine; D014162:Transfection; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D015850:Interleukin-6; D046911:Macromolecular Substances; D010703:Phorbol Esters; D011971:Receptors, Immunologic; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; C008876:phorbol-12,13-didecanoate; D003513:Cycloheximide; D011493:Protein Kinase C; D019311:Staurosporine