Extracellular signal-regulated kinases control expression of G protein-coupled receptor kinase 2 (GRK2).
G protein-coupled receptor kinase 2 (GRK2) phosphorylates G protein-coupled receptors resulting in uncoupling from G proteins. Receptors modulate GRK2 expression, however the mechanistic basis for this effect is largely unknown. Here we report a novel mechanism by which receptors use the extracellular signal-regulated kinase (ERK) cascade to regulate GRK2 cellular levels. ERK activation by receptor stimulation elevated endogenous GRK2 while antagonist treatment decreased cellular GRK2. Activating ERK by overexpressing constitutive active MEK-1 or Ras elevated GRK2 protein levels while blocking ERK using PD98059 or dominant negative Ras abolished this effect. These data suggest ERK is a critical regulator of GRK2 levels.
Theilade
Juliane
J
Laboratory for Molecular Cardiology and Department of Medicine B, Rigshospitalet 9312, University of Copenhagen, Juliane Mariesvej 20, DK-2100, Copenhagen, Denmark.
Lerche Hansen
Jakob
J
Haunsø
Stig
S
Sheikh
Søren P
SP
D000818:Animals; D000831:Animals, Newborn; D019556:COS Cells; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D054769:G-Protein-Coupled Receptor Kinase 2; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009154:Mutation; D009206:Myocardium / Q000201:enzymology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism; D015854:Up-Regulation; D051552:beta-Adrenergic Receptor Kinases
D004791:Enzyme Inhibitors; D005419:Flavonoids; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D017868:Cyclic AMP-Dependent Protein Kinases; C496569:Grk2 protein, rat; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one