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

Signaling from the activin/transforming growth factor beta (TGF beta) family of cytokines is a tightly regulated process. Disregulation of TGF beta 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 TGF beta-signaling cascade. TGF beta- induced expression of GRK2 acts in a negative feedback loop to control TGF beta biological responses. Upon TGFb 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 TGF beta- mediated target gene expression, cell growth inhibition and apoptosis. Furthermore, we demonstrate that GRK2 antagonizes TGF beta- 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.