Activation of Raf-1 signaling by protein kinase C through a mechanism involving Raf kinase inhibitory protein.
Protein kinase C (PKC) regulates activation of the Raf-1 signaling cascade by growth factors, but the mechanism by which this occurs has not been elucidated. Here we report that one mechanism involves dissociation of Raf kinase inhibitory protein (RKIP) from Raf-1. Classic and atypical but not novel PKC isoforms phosphorylate RKIP at serine 153 (Ser-153). RKIP Ser-153 phosphorylation by PKC either in vitro or in response to 12-O-tetradecanoylphorbol-13-acetate or epidermal growth factor causes release of RKIP from Raf-1, whereas mutant RKIP (S153V or S153E) remains bound. Increased expression of PKC can rescue inhibition of the mitogen-activated protein (MAP) kinase signaling cascade by wild-type but not mutant S153V RKIP. Taken together, these results constitute the first model showing how phosphorylation by PKC relieves a key inhibitor of the Raf/MAP kinase signaling cascade and may represent a general mechanism for the regulation of MAP kinase pathways.
Corbit
Kevin C
KC
Department of Neurobiology, Pharmacology and Physiology, and Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637, USA.
Trakul
Nicholas
N
Eves
Eva M
EM
Diaz
Bruce
B
Marshall
Mark
M
Rosner
Marsha Rich
MR
D000727:Androgen-Binding Protein; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D002461:Cell Line, Transformed; D018360:Crystallography, X-Ray; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D049488:Phosphatidylethanolamine Binding Protein; D049294:Phospholipid Transfer Proteins; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011493:Protein Kinase C / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D000099221:Protein Kinase C zeta
D000727:Androgen-Binding Protein; D002352:Carrier Proteins; D017931:DNA Primers; D004791:Enzyme Inhibitors; D049488:Phosphatidylethanolamine Binding Protein; D049294:Phospholipid Transfer Proteins; D011493:Protein Kinase C; D019908:Proto-Oncogene Proteins c-raf; D011993:Recombinant Fusion Proteins; D000099221:Protein Kinase C zeta; C511482:PEBP1 protein, human