Elsevier

Cellular Signalling

Volume 25, Issue 12, December 2013, Pages 2831-2839
Cellular Signalling

G protein-coupled receptor kinase 2 (GRK2) is a Rho-activated scaffold protein for the ERK MAP kinase cascade

https://doi.org/10.1016/j.cellsig.2013.08.031Get rights and content
Under a Creative Commons license
open access

Highlights

  • GRK2 is a novel RhoA effector.

  • RhoAGTP binding to GRK2 promotes GRK2 binding to Raf1, MEK1 and ERK2.

  • RhoA-activated ERK scaffolding by GRK2 enhances EGFR-dependent ERK activity.

Abstract

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.

Abbreviations

CNK1
connector enhancer of KSR-1
DGKθ
diacylglycerol kinase θ
EGF
epidermal growth factor
GIT
GRK-interacting protein
GPCR
G protein-coupled receptor
GRK
GPCR kinase
KSR-1
kinase suppressor of ras-1
MAPK
mitogen-activated protein kinase
PDEγ
phosphodiesterase-γ
PDGF
platelet-derived growth factor
PI3K
phosphoinositide 3-kinase
PKN
protein kinase N
ROCK
Rho-associated kinase
RTK
receptor tyrosine kinase
VSMC
vascular smooth muscle cell
RKIP
Raf kinase inhibitor protein

Keywords

G protein-coupled receptor kinase 2 (GRK2)
RhoA
Scaffold protein
ERK
Epidermal growth factor receptor (EGFR)

Cited by (0)