%0 Journal Article %1 Lorenz2003 %A Lorenz, K. %A Lohse, M. J. %A Quitterer, U. %D 2003 %J Nature %K & *Androgen-Binding 2 3 AMP-Dependent Animals Binding Brain/metabolism C/*metabolism Cardiac/metabolism Carrier Cell Cyclic Enzyme G-Protein-Coupled Humans Inhibitors/*metabolism Interference Kinase Kinases Kinases/*antagonists Line Mice Myocytes, Phosphatidylethanolamine Phospholipid Phosphorylation Precipitin Protein Proteins Proteins/genetics/*metabolism Proto-Oncogene RNA Rats Receptor Signal Specificity Substrate Tests Transduction Transfer Uteroglobin beta-Adrenergic c-raf/*antagonists inhibitors/genetics/metabolism %N 6966 %P 574-9 %T Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14654844 %V 426 %X 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.

@article{Lorenz2003, 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 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.}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Lorenz, K. and Lohse, M. J. and Quitterer, U.}, biburl = {https://www.bibsonomy.org/bibtex/2ec0e00522aeb4db22e031d6eab21028f/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {c7d907eccf8684ed9ecfd945703d53bc}, intrahash = {ec0e00522aeb4db22e031d6eab21028f}, issn = {1476-4687 (Electronic) 1476-4687 (Linking)}, journal = {Nature}, keywords = {& *Androgen-Binding 2 3 AMP-Dependent Animals Binding Brain/metabolism C/*metabolism Cardiac/metabolism Carrier Cell Cyclic Enzyme G-Protein-Coupled Humans Inhibitors/*metabolism Interference Kinase Kinases Kinases/*antagonists Line Mice Myocytes, Phosphatidylethanolamine Phospholipid Phosphorylation Precipitin Protein Proteins Proteins/genetics/*metabolism Proto-Oncogene RNA Rats Receptor Signal Specificity Substrate Tests Transduction Transfer Uteroglobin beta-Adrenergic c-raf/*antagonists inhibitors/genetics/metabolism}, month = {Dec 4}, note = {Lorenz, Kristina Lohse, Martin J Quitterer, Ursula Research Support, Non-U.S. Gov't England Nature Nature. 2003 Dec 4;426(6966):574-9.}, number = 6966, pages = {574-9}, shorttitle = {Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2}, timestamp = {2010-12-14T18:18:57.000+0100}, title = {Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14654844}, volume = 426, year = 2003 }