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P. PENELA Y COLS. AN. R. ACAD. NAC. FARM

NOVEL GRK2 FUNCTIONAL INTERACTIONS MIGHT BE
RELATED TO THE ROLE OF THIS KINASE IN INFLAMMATION

AND CELL MIGRATION

GRK2 as a modulator of the MEK/ERK interface upon chemokine
challenge

We have recently reported, using GRK2-transfected cells or
splenocytes from heterozygous GRK2 mice, that elevated levels of GRK2
can inhibit chemokine-mediated induction of ERK activity and, on the
contrary, that decreased levels of GRK2 promote a more robust ERK
activation upon agonist treatment. Neither the kinase activity of GRK2 nor
its interaction with G protein subunits is necessary for this inhibitory effect
and no changes were observed in the extent of MEK activation in our
experimental settings. Interestingly, we have found that GRK2 and MEK1
are present in the same multimolecular complex and that this interaction
correlates with an inhibition of ERK activation, that involves a direct or
coordinate interaction with MEK (26). Thus, this association seems to be
important in the control of chemokine induction of MAPK activation hence
for the extent of chemotactic cell motility. By binding to MEK, GRK2
could interfere (at the cellular level or at defined cellular locations) with
MEK association to proteins important for its cellular compartimentation,
internalization, or activity, such as MEK-ERK scaffolds. Therefore,
changes in GRK2 expression in pathological conditions would alter
chemokine receptor signaling at different levels.

GRK2/p38 MAPK
We have found that GRK2 directly phosphorylates p38a at the

Thr123 residue located at the entrance of the p38 docking groove (7).
Mimicking phosphorylation of this residue interferes with the binding and
phosphorylation of well-established p38 substrates (ATF2, MEF2, MK2),
and also with the ability of p38 to bind and become phosphorylated by
MKK6 in vitro and in cells. This phosphorylation has an impact on p38-
dependent cellular functions, since changing GRK2 levels alters the
secretion of TNFa upon LPS stimulation, this process being increased in
GRK2+/- murine macrophages.

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