title: The G protein-coupled receptor kinase-2 is a TGFbeta-inducible antagonist of TGFbeta signal transduction.
abstract: Signaling from the activin/transforming growth factor beta (TGFbeta) family of cytokines is a tightly regulated process. Disregulation of TGFbeta signaling is often the underlying basis for various cancers, tumor metastasis, inflammatory and autoimmune diseases. In this study, we identify the protein G-coupled receptor kinase 2 (GRK2), a kinase involved in the desensitization of G protein-coupled receptors (GPCR), as a downstream target and regulator of the TGFbeta-signaling cascade. TGFbeta-induced expression of GRK2 acts in a negative feedback loop to control TGFbeta biological responses. Upon TGFbeta stimulation, GRK2 associates with the receptor-regulated Smads (R-Smads) through their MH1 and MH2 domains and phosphorylates their linker region. GRK2 phosphorylation of the R-Smads inhibits their carboxyl-terminal, activating phosphorylation by the type I receptor kinase, thus preventing nuclear translocation of the Smad complex, leading to the inhibition of TGFbeta-mediated target gene expression, cell growth inhibition and apoptosis. Furthermore, we demonstrate that GRK2 antagonizes TGFbeta-induced target gene expression and apoptosis ex vivo in primary hepatocytes, establishing a new role for GRK2 in modulating single-transmembrane serine/threonine kinase receptor-mediated signal transduction.
authors.affiliation: Hormones and Cancer Research Unit, Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, Canada.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ho
authors.forename: Eftihia
authors.initials: E
authors.lastname: Cocolakis
authors.forename: Victor M
authors.initials: VM
authors.lastname: Dumas
authors.forename: Barry I
authors.initials: BI
authors.lastname: Posner
authors.forename: Stéphane A
authors.initials: SA
authors.lastname: Laporte
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lebrun
mesh_terms: D021581:Active Transport, Cell Nucleus; D028341:Activins / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009638:Norepinephrine / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein; D051900:Smad3 Protein; D013379:Substrate Specificity; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D051552:beta-Adrenergic Receptor Kinases
chemical_list: D004268:DNA-Binding Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D028341:Activins; D017868:Cyclic AMP-Dependent Protein Kinases; C496569:Grk2 protein, rat; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D009638:Norepinephrine