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Publication Detail
G protein-coupled receptor kinase 2 (GRK2) is a Rho-activated scaffold protein for the ERK MAP kinase cascade
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Pitcher JA, Robinson, JR
  • Publication date:
  • Status:
  • Translators:
  • Keywords:
    G protein-coupled receptor kinase 2 (GRK2), RhoA, scaffold protein, epidermal growth factor (EGF).
The G protein-coupled receptor kinases (GRKs) are best known for their role in phosphorylating and desensitizing G protein-coupled receptors (GPCRs). The GRKs also regulate signaling downstream of other families of receptors and have a number of non-receptor substrates and binding partners. Here we identify RhoAGTP and Raf1 as novel binding partners of GRK2 and report a previously unsuspected function for this kinase. GRK2 is a RhoA effector that serves as a RhoA-activated scaffold protein for the ERK MAP kinase cascade. The ability of GRK2 to bind to Raf1, MEK1 and ERK2 is dependent on RhoAGTP binding to the catalytic domain of the kinase. Exogenous GRK2 has previously been shown to increase ERK activation downstream of the epidermal growth factor (EGF) receptor. Here we find that GRK2-mediated ERK activation downstream of the EGF receptor is Rho-dependent and that treatment with EGF promotes RhoAGTP binding and ERK scaffolding by GRK2. Depletion of GRK2 expression by RNAi reveals that GRK2 is required for EGF-induced, Rho- and ERK-dependent thymidine incorporation in vascular smooth muscle cells (VSMCs). We therefore hypothesize that Rho-dependent ERK MAPK scaffolding by GRK2 downstream of the EGF receptor may have an important role in the vasculature, where increased levels of GRK2 and RhoA have been associated with hypertension.
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