Page 71 - 74_04

VOL. 74 (4) ROLE OF G PROTEIN-COUPLED RECEPTOR ...

Kinases upstream p38 have been classically involved in its
activation by means of phosphorylation at the activation loop, but this
work defines GRK2 as a kinase upstream of p38 and also as an
“inactivating MAP2K”, what may have important consequences in the
regulation of p38 activation subsequent to stimuli that potentiate GRK2
activity, such as GPCRs. Accordingly, one may envisage a scenario where
previous GPCR stimulation could lead to an increased pool of pT123-p38
and thus serve to dampen subsequent p38 stimulation by other stimuli. In
support of this notion, p38 activity happens to be reduced in end stage
failing myocardium in humans while the elevation of GRK2 levels is an
early event in cardiac failure (see ref. (27) for a review). In striking
accordance, activation of p38 has long been shown to be critical for the
development of various inflammatory processes including rheumatoid
arthritis, pulmonary illnesses and inflammatory bowel disease (28).
Precisely, as mentioned above, a significant reduction of GRK2 levels was
described in animal models of adjuvant-induced arthritis (21), or human
rheumatoid arthritis and multiple sclerosis (20, 23), what also points to a
negative correlation between GRK2 levels and p38 activity, and a
functional role for GRK2 in the control of p38 activation, that might be
altered in inflammatory conditions.

GRK2/GIT
The GIT family of proteins display a complex domain structure,

including a zinc-finger motif, three ankyrin repeats present in the N-
terminal region of the protein, a Spa2-homology domain (SHD), a coiled-
coiled domain and a paxillin-binding site (PBS). As a result of such
multidomain architecture, GIT proteins can interact with a variety of
signalling molecules involved in multiple cellular processes as cytoskeletal
dynamics, membrane trafficking, cell adhesion and signal scaffolding (29).
Therefore, the GRK2/GIT1 interaction may be involved in the modulation
of cell migration processes (5). However, only recently the functional
consequences and the modulation of such interaction by extra-cellular
signals have been addressed. Our laboratory has found that GRK2
positively regulates epithelial cell migration by mechanisms involving
coordinated fibronectin and S1P-mediated signalling and the modulation of
the Rac/PAK/MEK/ERK1/2 pathway in response to S1P and adhesion,

11