Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2

• Published in: Nature 2003-12, Vol.426 (6966), p.574-579
• Main Authors: Quitterer, Ursula, Lorenz, Kristina, Lohse, Martin J
• Format: Article
• Language: English
• Subjects: Androgen-Binding Protein; Animals; beta-Adrenergic Receptor Kinases; Biological and medical sciences; Brain - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Cell physiology; Cellular biology; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Enzyme Inhibitors - metabolism; Enzymes; Fundamental and applied biological sciences. Psychology; G-Protein-Coupled Receptor Kinase 2; G-Protein-Coupled Receptor Kinase 3; Humanities and Social Sciences; Humans; Hypertension; letter; Mammals; Mice; Molecular and cellular biology; multidisciplinary; Myocytes, Cardiac - metabolism; Phosphatidylethanolamine Binding Protein; Phospholipid Transfer Proteins; Phosphorylation; Physiology; Precipitin Tests; Prostatein; Protein Binding; Protein Kinase C - metabolism; Proteins; Proto-Oncogene Proteins c-raf - antagonists & inhibitors; Proto-Oncogene Proteins c-raf - genetics; Proto-Oncogene Proteins c-raf - metabolism; Rats; RNA Interference; Science; Science (multidisciplinary); Secretoglobins; Signal Transduction; Substrate Specificity; Uteroglobin
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature02158

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 β-adrenergic signalling and contractile activity.