The diverse roles of G protein-coupled receptor kinase 2 (GRK2): a focus on regulation of receptor tyrosine kinases (RTKs)

Abstract

The G protein-coupled receptor (GPCR) kinases (GRKs) are a family of seven serine/threonine kinases that are recruited to and activated by almost all agonist-occupied GPCRs. Upon recruitment and activation, GRK2 inhibits G protein-dependent signaling downstream of GPCRs both directly, for example by sequestering activated G proteins, and indirectly, by promoting the recruitment of ?-arrestins, which sterically hinder further G protein activation and drive receptor internalization. In addition to switching off G protein signaling, GRK2 also initiates a number of G protein-independent signaling pathways downstream of activated GPCRs by recruiting scaffolding proteins or by phosphorylating non-GPCR substrates. Furthermore, it has recently become clear that the GRKs regulate signaling downstream of receptors that belong to families other than the GPCRs, including the transforming growth factor ? (TGF?) receptor and the toll-like receptor TLR4. Here we focus on recent studies demonstrating an important role for GRK2 in regulating signaling in both positive and negative ways downstream of various receptor tyrosine kinases (RTKs), including platelet-derived growth factor (PDGF) receptors, epidermal growth factor (EGF) receptors and insulin-like growth factor 1 (IGF-1) receptors.