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

classically serves to re-sensitize and recycle receptors back to the plasma
membrane, but may also help to promote the activation of additional
signalling pathways by way of arrestins and/or GRKs acting as agonist-
regulated adaptor scaffolds (4, 5). Interestingly, GRK2 expression and
function has been shown to be altered in several inflammatory conditions
(see below), thus suggesting that it may play an important role in the onset
or progression of the inflammatory disease. Therefore, the understanding
of the molecular mechanisms leading to altered GRK2 levels and
functionality, as well as of the consequences of such changes on key
cellular processes is a very active field of research.

Consistent with its role in GPCR desensitization, GRK2 has been
shown to attenuate chemokine-induced migration in T cells and monocytes
(revised in (6)), thus emerging as a relevant modulator of inflammatory

responses. However, pro-migratory effects for ß-arrestins and for a
member of a distinct GRK subfamily, GRK6, have also been reported in
response to different GPCR in several cell types (2, 6), thereby suggesting
other unknown functional roles different to those related to GPCR
desensitization.

Interestingly, in addition to phosphorylate a variety of GPCR,
recent data indicate that GRK2 is also able to phosphorylate other types of
membrane receptors, such as the PDGF-receptor, and non-receptor
substrates as tubulin, the ERM family protein ezrin, or the p38 MAPK (see
(4, 5, 7) and references therein). Thus, GRK2 may participate in the
regulation of diverse cellular phenomena through the phosphorylation of
substrates that are very varied functionally. Moreover, GRK2 has been
shown to interact with a variety of proteins involved in migration (MEK,
Akt, PI3K? or GIT (reviewed in (5)). In this review we will briefly
summarize the main mechanisms involved in the control of GRK2
expression and function, its reported alterations in inflammatory disorders
and the emerging functional interactions of GRK2 with diverse molecules
related to cell migration and inflammation (see Figure 1) that may shed
new light on how GRK2 influences motility in different cellular types and
on the physiological consequences of altering the cellular complement of
this kinase.

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