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and the phosphorylation of GRK2 on critical tyrosine residues (11).
MAPK-mediated GRK2 phosphorylation also triggers GRK2 degradation

in a process which is again dependent on ß-arrestin function (17). More
recently, we have shown that Mdm2, an E3-ubiquitin ligase involved in the
control of cell growth and apoptosis, plays a key role in GRK2 degradation
(18). Mdm2 and GRK2 association and subsequent proteolysis is enhanced

by ß2-adrenergic receptor stimulation and ß-arrestin. On the contrary,
activation of the PI3K/Akt pathway by agonists such as IGF-1 alters
Mdm2-mediated GRK2 degradation, leading to enhanced GRK2 stability
and increased kinase levels, what might be relevant in several
pathophysiological contexts.

FIGURE 2.- Mechanisms involved in the regulation of GRK2 stability. See text for details.

GRK2 levels might also be downregulated by additional proteolytic
pathways. Rheumatoid arthritis (RA) patients display significantly reduced
GRK2 levels in peripheral blood mononuclear cells (PBMC) without
significant changes in GRK mRNA levels. The same is observed in rats in
an animal model of adjuvant arthritis (6). Proinflammatory cytokines as
IL-6 and INF? are elevated in patients with RA, and treatment of PBMC
with these compounds strongly promotes GRK2 down-regulation.

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