The G protein-coupled receptor kinases (GRKs) are best known for their role in 
phosphorylating and desensitising G protein-coupled receptors (GPCRs). The GRKs 
also regulate signalling 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 receptor 
(EGFR). Here we find that GRK2-mediated ERK activation downstream of the EGFR 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 hypothesise that 
Rho-dependent ERK MAPK scaffolding by GRK2 downstream of the EGFR may have an 
important role in the vasculature, where increased levels of both GRK2 and RhoA 
have been associated with hypertension.