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

stimulation of ß2-adrenergic receptors (10). This process is dependent on
the ability of ß-arrestins to recruit c-Src (11). The activity of tyrosine-
phosphorylated GRK2 is increased toward both soluble and membrane-
bound substrates, suggesting a direct effect on its catalytic activity.
Mutagenesis experiments have identified tyrosine residues within the RH
region of GRK2 (amino acids 13, 86 and 92) that are critical for c-Src-
mediated phosphorylation. Tyrosine phosphorylation also appears to

enhance the interaction of GRK2 with Gaq (12) and to promote its
degradation by the proteasome pathway (see below).

GRK2 activity is also regulated by p42/p44 MAPK. “In vitro” and
“in situ” experiments revealed that ERK1 is able to phosphorylate
recombinant GRK2 on serine 670 (13, 14), and both kinases are
specifically co-immunoprecipitated in an agonist-dependent manner (13).

Interestingly, Serine 670 lies within the Gß? binding domain of GRK2, and
MAPK phosphorylation of this site strongly impairs the GRK2/Gß?
interaction, thereby inhibiting kinase translocation and catalytic activity
toward receptor membrane substrates.

REGULATION OF GRK2 EXPRESSION LEVELS

Little has been reported about the mechanisms governing GRK
transcription. In aortic smooth muscle cells, agents that induce
physiological vasoconstriction and hypertrophy markedly enhance GRK2
promoter activity, whereas pro-inflammatory cytokines promote the
opposite effect, suggesting that the expression of GRK2 is strongly
controlled at the transcriptional level by the interplay between various
signal transduction pathways (15). However, whether these mechanisms
apply to other cell types awaits further investigation.

On the other hand, regulation of GRK2 stability may provide an
important mechanism for modulating its expression levels (Figure 2).
GRK2 is rapidly degraded by the proteasome pathway, and ß2AR
activation enhances GRK2 ubiquitination and turnover (16). Our
laboratory has also shown that agonist-dependent binding of ß-arrestin to
GPCR supports GRK2 degradation by allowing the recruitment of c-Src

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