Arrestins in Actin Reorganization and Cell Migration - Progress in Molecular Biology and Translational Science - page 204

seeds. Actin nucleators can also bind to the sides of existing filaments to facil-
itate branching of actin filaments such as make up the broad lamellipodia of
the leading edge. These processes are essential to provide directionality dur-
ing migration, as well as for the assembly and maintenance of cortical actin
filaments that interact with contractile proteins. Cortical actin filaments
allow the cell to contract against the substrate over which it is migrating.
These actin structures must be dynamically remodeled, requiring an intricate
balance of input from various signaling pathways. We will now examine
these different processes, the proteins that drive them and the reported role
of b -arrestins.
3.1. The cofilin pathway: Creating new actin seeds
Proteins of the cofilin pathway (cofilin, chronophin, slingshot, and LIM
kinase (LIMK)) have long been known to play crucial roles in establishing
a leading edge downstream of multiple receptors. Cofilin is one of the pri-
mary actin filament severing proteins and its activation is often an early event
in cell migration. 7,8 Cofilin is activated by dephosphorylation on serine 3,
carried out by the phosphatases slingshot and chronophin and inactivated
by LIMK. Dephosphorylated cofilin binds to the side of actin filaments,
destabilizing them such that they break apart creating multiple actin seeds
to which actin monomers can add. Evidence that all of these proteins bind
b -arrestins has led to the hypothesis that b -arrestins are responsible for spatial
control of their activities. The dendritic model for actin remodeling predicts
that cofilin rapidly disassembles existing filaments, providing free barbed
ends for elongation and, in coordination with activation of nucleating pro-
teins, can lead to the formation of a leading edge that drives the direction of
cell migration. 8 Spatial control over cofilin activity is essential to allow for
treadmilling of filaments. Two GPCRs, PAR2 and AT1AR, 9-11 have been
shown to promote b -arrestin-dependent cofilin activation through scaffold-
ing of its upstream regulators. b -Arrestins can also bind LIMK and inhibit its
activity downstream of PAR2, to facilitate cofilin dephosphorylation. 9
Association with b -arrestin also facilitates dephosphorylation of cofilin by
chronophin and slingshot, and localizes cofilin activity to the leading edge
of the cell to promote barbed-end formation and membrane protrusion 10,11
( Fig. 8.2 ). This b -arrestin/cofilin scaffold is important for leukocyte migra-
tion and may contribute to extravasation of leukocytes into tissue during
inflammation. 10 When cofilin activity is not spatially controlled, protrusions
can form randomly and cells lose their ability to move toward a chemotactic