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

Nature | Dec 4, 2003

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.

Pubmed ID: 14654844 RIS Download

Mesh terms: Androgen-Binding Protein | Animals | Brain | Carrier Proteins | Cell Line | Cyclic AMP-Dependent Protein Kinases | Enzyme Inhibitors | G-Protein-Coupled Receptor Kinase 2 | G-Protein-Coupled Receptor Kinase 3 | Humans | Mice | Myocytes, Cardiac | Phosphatidylethanolamine Binding Protein | Phospholipid Transfer Proteins | Phosphorylation | Precipitin Tests | Prostatein | Protein Binding | Protein Kinase C | Proto-Oncogene Proteins c-raf | RNA Interference | Rats | Secretoglobins | Signal Transduction | Substrate Specificity | Uteroglobin | beta-Adrenergic Receptor Kinases

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