Arrestins in Actin Reorganization and Cell Migration - Progress in Molecular Biology and Translational Science - page 200

1. INTRODUCTION
Cell migration requires a number of spatially controlled events involv-
ing reorganization of the actin cytoskeleton, formation of a leading edge,
assembly and disassembly of focal contacts, and contraction of the cell cor-
tex. Actin cytoskeletal reorganization and cell migration, downstream of
numerous receptors, require either or both b -arrestins, leading to a great deal
of interest in the mechanism by which they regulate these processes. 1 The
first step in cell migration involves the sensing of a gradient. While many
cells can randomly migrate through a uniform concentration of agonist
due to the activation of receptors that mediate morphological changes,
the ability to sense a gradient is the first step for most cell migration pathways
in vivo . The second step is the formation of a leading edge, which involves
reorganization of the actin cytoskeleton and disassembly of focal contacts.
Third, new focal contacts are formed and the cortex contracts, dragging
the cell body forward. This process continues until the cell reaches the
chemokine source. Once it is surrounded by a high concentration of the
chemokine and the cell no longer senses a gradient, migration will cease. 2
b -Arrestins have been implicated at all stages of this process: b -arrestin scaf-
folds have been implicated in actin assembly events necessary for the forma-
tion of gradient-sensing filipodia and the lamellipodia of the leading edge.
Additionally, b -arrestin-dependent desensitization of chemokine receptors
in response to high concentrations of agonist has been implicated in
the ability of migrating immune cells to sense a chemokine gradient
( Fig. 8.1 ). Impaired desensitization results in random rather than directed
migration. Finally, b -arrestins scaffold a number of proteins involved in
endocytosis and many of the signaling proteins regulated by b -arrestins
require endocytotic machinery for correct subcellular localization. Thus,
while the differing roles of b -arrestin signaling and endocytosis in cell migra-
tion and cytoskeletal regulation can be separated in vitro , they are likely
inseparable in vivo .
2. b -ARRESTINS AS REGULATORS OF GRADIENT
SENSING FOR CHEMOKINE RECEPTORS
Cancer cells and immune cells both migrate toward a chemotactic
agent and a primary receptor family that mediates this migration is the che-
mokine receptor family. Chemokine receptors are GPCRs and a number