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.
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
Nature
Date: Dec. 04, 2003
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