Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 124

proliferation. D2 dopamine receptor activation of the NF- k B pathway
reportedly requires c-Src as well as G a i proteins, and this response is
potentiated by overexpression of arrestin2. 80 c-Src is also recruited to
rhodopsin-arrestin1 complexes, which concentrate in the rod outer segment
compartment upon light exposure. 73 It has been proposed that c-Src binding
to arrestin1 promotes the formation of high-affinity phospho-Tyr
binding sites in the rod outer segment that lead to translocation of SH2-
containing proteins.
4.1.2 Receptor tyrosine kinases
Members of EGF receptor family of receptor tyrosine kinases (HER1-4) are
key convergence points for mitogenic stimuli. A well-characterized mech-
anism whereby GPCRs affect cell proliferation and survival is by stimulating
the matrix metalloprotease (MMP)-dependent shedding of preformed EGF-
family growth factors, leading to paracrine transactivation of EGF receptors
(reviewed in Ref. 81 ). In some settings, arrestin-Src complexes play a role in
GPCR-mediated EGF receptor transactivation, and arrestin-dependent
activation of the ERK1/2 cascade downstream of transactivated EGF recep-
tors can stimulate transcription and promote cell proliferation. This contrasts
with direct arrestin-dependent scaffolding mechanism of ERK1/2 activa-
tion, wherein the signalsome-bound active ERK1/2 is usually transcription-
ally repressed. 25,46
The luteinizing hormone (LH) receptor activates c-Fyn in an arrestin3-
dependent manner. 61 Downregulating arrestin expression reduces the rate
of internalization of hCG by 50% and inhibits LH receptor-mediated acti-
vation of c-Fyn, phosphorylation of the antiapoptotic focal adhesion kinase
(FAK), and the release of EGF-like growth factors. In HEK293 cells
expressing b 1-adrenergic receptors, EGF receptor transactivation and
ERK1/2 activation are inhibited by downregulation of arrestin2 or 3, or
GRK5 or 6, inhibiting Src or MMP activity, or exposure to a heparin-
binding-EGF neutralizing antibody, suggesting that b 1-receptor-mediated
EGF receptor transactivation is arrestin dependent. 62 Consistent with this,
a mutant b 1-receptor lacking 14 GRK phosphorylation sites in its
C-terminal tail (-GRK b 1), which cannot undergo arrestin-dependent
desensitization, fails to transactivate EGF receptors despite exaggerated
G protein activation. Transgenic mice expressing the -GRK b 1 receptor
in cardiomyocytes develop more severe dilated cardiomyopathy in response
to chronic isoproterenol stimulation, with significantly increased LV
end-diastolic dimension, decreased fractional shortening, and increased