Arrestins in Actin Reorganization and Cell Migration - Progress in Molecular Biology and Translational Science - page 208

A

b -Arrestin

P

P

Actin

P

RHOGEF

P

P

P

PIP3

P

P

P

PI3K

Cdc42 RhoA

Rac

B

Filamin

Ral A

Ral-GDS

Ral-GDS

Figure 8.3 Model for regulation of RhoA GTPases by b -arrestins. (A) Upon binding to a
variety of GPCRs, b -arrestins can indirectly facilitate the activity of PI3K or directly inhibit
its activity. PIP3, the product of PI3K activity, can then activate a number of GEFs for the
Rho GTPases, Cdc42, Rac and RhoA. In this fashion, b -arrestins can either activate or
inhibit Rho GTPase activity in a manner dependent upon the activating receptor.
(B) -Arrestin-2 binds constitutively to the guanine exchange factor for the GTPase,

Ral1 (Ral-GDS). Upon binding to the activated fMLP receptor, Ral-GDS is released and
free to activate membrane-associated Ral, which associates with filamin to promote
actin filament reorganization and membrane blebbing.

b

4. REGULATION OF KINASE ACTIVITIES BY b -ARRESTINS
b -Arrestins are required for ERK1/2 and JNK activation downstream
of numerous GPCRs, and b -arrestins can sequester ERK1/2 activity within
the leading edge of migrating cells. Furthermore, b -arrestins can facilitate
activation of Src and other non-receptor-tyrosine kinases and can both acti-
vate and inhibit PI3Ks. Because both ERK1/2 and b -arrestins are required
for cell migration downstream of many of these receptors, it is likely that