Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2.
Feedback inhibition is a fundamental principle in signal transduction allowing rapid adaptation to different stimuli. In mammalian cells, the major feedback inhibitor for G-protein-coupled receptors (GPCR) is G-protein-coupled receptor kinase 2 (GRK-2), which phosphorylates activated receptors, uncouples them from G proteins and initiates their internalization. The functions of GRK-2 are indispensable and need to be tightly controlled. Dysregulation promotes disorders such as hypertension or heart failure. In our search for a control mechanism for this vital kinase, here we show that the Raf kinase inhibitor protein (RKIP) is a physiological inhibitor of GRK-2. After stimulation of GPCR, RKIP dissociates from its known target, Raf-1 (refs 6-8), to associate with GRK-2 and block its activity. This switch is triggered by protein kinase C (PKC)-dependent phosphorylation of the RKIP on serine 153. The data delineate a new principle in signal transduction: by activating PKC, the incoming receptor signal is enhanced both by removing an inhibitor from Raf-1 and by blocking receptor internalization. A physiological role for this mechanism is shown in cardiomyocytes in which the downregulation of RKIP restrains beta-adrenergic signalling and contractile activity.
Lorenz
Kristina
K
Institut für Pharmakologie und Toxikologie, Versbacher Strasse 9, D-97078 Würzburg, Germany.
Lohse
Martin J
MJ
Quitterer
Ursula
U
D000727:Androgen-Binding Protein; D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D054769:G-Protein-Coupled Receptor Kinase 2; D054770:G-Protein-Coupled Receptor Kinase 3; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D049488:Phosphatidylethanolamine Binding Protein; D049294:Phospholipid Transfer Proteins; D010766:Phosphorylation; D011233:Precipitin Tests; D060789:Prostatein; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D060765:Secretoglobins; D015398:Signal Transduction; D013379:Substrate Specificity; D014598:Uteroglobin; D051552:beta-Adrenergic Receptor Kinases; D060788:Mammaglobin B
D000727:Androgen-Binding Protein; D002352:Carrier Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D054769:G-Protein-Coupled Receptor Kinase 2; D054770:G-Protein-Coupled Receptor Kinase 3; D049488:Phosphatidylethanolamine Binding Protein; D049294:Phospholipid Transfer Proteins; D060789:Prostatein; D011493:Protein Kinase C; D019908:Proto-Oncogene Proteins c-raf; D060765:Secretoglobins; D014598:Uteroglobin; D051552:beta-Adrenergic Receptor Kinases; C511482:PEBP1 protein, human; C511484:Scgb1d2 protein, rat; C511483:Scgb1d4 protein, rat; C517848:GRK3 protein, human; C517850:GRK3 protein, mouse; C496569:Grk2 protein, rat; C517851:Grk3 protein, rat; C556468:Scgb2a1 protein, rat; D060788:Mammaglobin B