Arrestins in Actin Reorganization and Cell Migration - Progress in Molecular Biology and Translational Science - page 209

ERK1/2 might phosphorylate proteins important for cell migration, altering
their activity. The search for candidate targets of b -arrestin-dependent
ERK1/2 activity is ongoing, but phosphoproteomics screens have identified
a number of putative candidates. Some of these ERK1/2 targets are actin
nucleators andWiscott-Aldrich syndrome proteins (WASps), focal adhesion
proteins, and cofilin.

4.1. -Arrestin-dependent ERK1/2 activity

Despite the mystery as to what ERK1/2 is doing at the leading edge to
enhance cell motility, there is a significant body of evidence pointing to
an essential role for b -arrestin-sequestration of ERK1/2 in chemotaxis.
Many of the receptors first demonstrated to promote b -arrestin-dependent
ERK1/2 activation also require both for chemotaxis. We previously dis-
cussed chemokine receptors as prime examples of utilizing b -arrestins for
receptor turnover. However, not only can CXCR4 respond differently
to monomers versus dimers of its ligand, CCL12, but it can also form
heterodimers with the decoy receptor CXCR7, leading to dominance of
b -arrestin-dependent ERK1/2 phosphorylation and chemotaxis over
G-protein signaling. 30 Thus, CXCR4 stands out as an argument for the
importance of both the ERK1/2 scaffolding and internalization functions
of b -arrestins in chemotaxis. A number of proteins involved in actin assem-
bly have been identified as b -arrestin-dependent ERK1/2 phosphorylation
targets; however, for most of these, a definitive role in chemotaxis down-
stream of b -arrestins has not been proven.

b

4.1.1 Proposed role of ERK1/2 in actin nucleation
Regulation of actin nucleation by b -arrestins has not been directly shown,
although several proteins involved in actin nucleation have been identified as
b -arrestin-dependent ERK1/2 targets. Arp2/3 complex components and
WASp-family proteins have been identified in a proteomics screen as poten-
tial b -arrestin interacting proteins 5 and phosphorylation targets of MAPK 31
and activation of WASp-family proteins is enhanced by ERK1/2 phosphor-
ylation. The Arp2/3 complex, along with formins and p150spir, are the
primary nucleation factors in mammalian cells. 32,33 Arp2/3 is crucial
for the formation of branched actin filaments such as are observed in the
leading edge of migrating cells. Activation by WASps, which bind Arp2/
3 and induce a conformational change resulting in apposition of Arp2
and 3, is essential for the formation of branched filaments. Patients with
Wiscott-Aldrich syndrome have defective lymphocyte trafficking and