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

Kristina Lorenz, Martin J. Lohse and Ursula Quitterer ()
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Kristina Lorenz: Institut für Pharmakologie und Toxikologie
Martin J. Lohse: Institut für Pharmakologie und Toxikologie
Ursula Quitterer: Institut für Pharmakologie und Toxikologie

Nature, 2003, vol. 426, issue 6966, 574-579

Abstract: Abstract 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 internalization1,2. The functions of GRK-2 are indispensable and need to be tightly controlled3. Dysregulation promotes disorders such as hypertension4 or heart failure5. In our search for a control mechanism for this vital kinase, here we show that the Raf kinase inhibitor protein6,7,8 (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.

Date: 2003
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DOI: 10.1038/nature02158

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