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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.

Pubmed ID: 14654844


  • Lorenz K
  • Lohse MJ
  • Quitterer U



Publication Data

December 4, 2003

Associated Grants


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