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

Nature volume 426, pages 574–579 (2003)Cite this article

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.

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Figure 1: RKIP inhibits GRK-2-mediated GPCR phosphorylation.
Figure 2: The RKIP-mediated inhibition of GRK-2 correlates with enhanced signalling and decreased internalization.
Figure 3: PKC switches RKIP from Raf-1 to GRK-2.
Figure 4: Endogenously expressed RKIP enhances receptor-stimulated signalling.

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Acknowledgements

We thank W. Kolch for RKIP cDNA plasmids, M. Hoffmann for technical assistance, C. Dees for purification of GRK-2, M. Philipp for help with mouse tissue preparation, H. Mischak for PKCα and PKCδ, N. Burkard and S. Oberdorf-Maass for assistance in preparing cardiomyocytes, and S. Freund for determination of cardiomyocyte beating frequency. This work was supported by the Deutsche Forschungsgemeinschaft.

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  1. Institut für Pharmakologie und Toxikologie, Versbacher Strasse 9, D-97078, Würzburg, Germany

    Kristina Lorenz, Martin J. Lohse & Ursula Quitterer

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  1. Kristina Lorenz
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  2. Martin J. Lohse
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  3. Ursula Quitterer
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Correspondence to Ursula Quitterer.

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Lorenz, K., Lohse, M. & Quitterer, U. Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. Nature 426, 574–579 (2003). https://doi.org/10.1038/nature02158

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