Arrestins in Actin Reorganization and Cell Migration - Progress in Molecular Biology and Translational Science - page 210

function, due in part to the disruption of actin nucleation. These studies
have raised the possibility that b -arrestin-dependent phosphorylation of
WASp-family proteins might play a role in chemotaxis. 34,35 The actin
nucleating proteins, formins and p150spir, are primarily responsible for
de novo assembly of unbranched actin filaments. 33 Recently, a formin-like
protein was also identified as a putative b -arrestin-dependent phosphoryla-
tion target. 31 In the years to come, a more definitive role for regulation of
actin nucleation by b -arrestins may emerge.

4.1.2 ERK1/2 phosphorylation of other actin assembly proteins
Another protein identified as a putative b -arrestin-dependent ERK1/2 sub-
strate in two separate proteomics screens is, the barbed-end capping protein,
adducin. Phosphorylation of adducin by ser/thr kinases, PKC and Rho-
activated kinase(ROCK), diminishes its affinity for actin, increasing the pool
of free barbed ends and facilitating actin polymerization. Thus, phosphory-
lation by ERK1/2 may have a similar effect. Cofilin was also identified as a
b -arrestin-dependent ERK1/2 substrate. The known regulatory site on
cofilin (S3) was not the site identified in the phosphoproteomics screen.
Thus, if ERK1/2 phosphorylation contributes to b -arrestin-dependent
coflin dephosphorylation, it would be through a distinct mechanism, possi-
bly by stabilizing the active form.

4.2. -Arrestin/Src complexes and chemotaxis

Src was identified as a b -arrestin-binding partner downstream of several
GPCRs, linking them to ERK1/2 activation. 36 Downstream of prostaglan-
din E2 (PGE2) receptor, cell migration involves b -arrestin-dependent
recruitment of Src into a signaling complex that then transactivates the
epidermal growth factor receptor. 37 Similar b -arrestin-dependent trans-
activation pathways have been linked to proliferation as well. In another
example, activation of CCR5 with MIP1 leads to recruitment of Pyk2,
the p85 regulatory subunit of PI3K, and the tyrosine kinase, Lyn, into a
complex with b -arrestin-2 that is thought to be essential for macrophage
chemotaxis. 38 In these examples, the role of b -arrestins is relatively indirect,
essentially linking a GPCR-elicited signal to a tyrosine kinase cascade.
Whether these complexes are localized to the leading edge or lead to spatial
regulation of actin assembly proteins has not been examined.

b