Protein kinase C switches the Raf kinase inhibitor from Raf-1 to
GRK-2
K. Lorenz, M. Lohse, and U. Quitterer. Nature, 426 (6966):
574-9(December 2003)Lorenz, Kristina Lohse, Martin J Quitterer, Ursula Research Support,
Non-U.S. Gov't England Nature Nature. 2003 Dec 4;426(6966):574-9..
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.
%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
}