The G protein-coupled receptor kinase-2 is a TGFbeta-inducible antagonist of TGFbeta signal transduction

• Published in: The EMBO journal 2005-09, Vol.24 (18), p.3247
• Main Authors: Ho, Joanne, Cocolakis, Eftihia, Dumas, Victor M, Posner, Barry I, Laporte, Stéphane A, Lebrun, Jean-Jacques
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Activins - pharmacology; Animals; Apoptosis - drug effects; beta-Adrenergic Receptor Kinases; Cell Nucleus - metabolism; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; G-Protein-Coupled Receptor Kinase 2; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Humans; Norepinephrine - pharmacology; Phosphorylation; Protein Binding; Rats; Signal Transduction - drug effects; Smad2 Protein; Smad3 Protein; Substrate Specificity; Trans-Activators - genetics; Trans-Activators - metabolism; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology
• ISSN: 0261-4189
• DOI: 10.1038/sj.emboj.7600794

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.