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signal from the monomers. While CXCL12 monomers can promote
b
-arrestin recruitment and elicit
b
-arrestin-dependent signals such as actin
assembly and chemotaxis, the dimers do not. Thus, in addition to simply
promoting receptor turnover,
b
-arrestins may mediate the primary chemo-
tactic signal at lower CXCL12 concentrations and their signaling may be
dampened at higher concentrations, contributing to the cell's ability to sense
a gradient. These studies are particularly interesting as they suggest that
altered forms of the chemokines observed at high concentrations, rather than
receptor desensitization, play a role in the inhibition of cell migration
observed as cells reach the higher end of the concentration gradient. It is
important to note that there is a reciprocal relationship between endocytosis
and the scaffolding functions of
b
-arrestins discussed in the remainder of this
chapter.
b
-Arrestins can form scaffolds containing proteins involved in actin
assembly in response to activation of receptors that promote cell migration,
and these scaffolds can facilitate the formation of protrusions that initiate
movement toward the chemoattractant. Simultaneously,
b
-arrestins can
facilitate internalization of these same receptors through association with
endocytotic machinery.
3.
b
-ARRESTINS AS REGULATORS OF ACTIN ASSEMBLY
Other GPCRs, such as protease-activated receptor-2 (PAR2) and
angiotensin receptor (AT1AR), have been demonstrated to promote the
formation of
b
-arrestin scaffolds containing key actin assembly proteins,
supporting a model wherein active
b
-arrestin signaling is involved in che-
motaxis.
b
-Arrestins are required for both actin reorganization and chemo-
taxis by these and other GPCRs. Actin assembly within a cell is the primary
driving force behind directed cell movement and can be regulated, both
directly and indirectly, by various proteins. Actin polymerization from
monomers is a spontaneous but slow process and the rate-limiting step is
the formation of a stable nucleus, or actin seed, consisting of three or more
actin monomers. Addition of actin monomers is always at the ATP-binding
or barbed end of the actin molecule. Provided that the barbed end of a fil-
ament is free from capping proteins, addition of monomers onto pre-
assembled filaments or actin seeds is very rapid. These seeds can be
created in two major ways: (1) activation of proteins that break existing fil-
aments into smaller fragments creating a free barbed end at each break or (2)
activation of nucleators, that is, proteins that overcome the rate-limiting step
in actin assembly by facilitating association of actin monomers into filament
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