β-Arrestin-Dependent Actin Reorganization: Bringing the Right Players Together at the Leading Edge

Abstract

First identified as mediators of G-protein-coupled receptor desensitization and internalization and later as signaling platforms, ␤-arrestins play a requisite role in chemotaxis and reorganization of the actin cytoskeleton, downstream of multiple receptors. However, the precise molecular mechanisms underlying their involvement have remained elusive. Initial interest in ␤-arrestins as facilitators of cell migration and actin reorganization stemmed from the known interplay between receptor endocytosis and actin filament formation, because disruption of the actin cytoskeleton inhibits these ␤-arrestin-dependent events. With growing interest in the mechanisms by which cells can sense a gradient of agonist during cell migration, investigators began to hypothesize that ␤-arrestins may contribute to directed migration by controlling chemotactic receptor turnover at the plasma membrane. Finally, increasing evidence emerged that ␤-arrestins are more than just clathrin adaptor proteins involved in turning off receptor signals; they are actually capable of generating their own signals by scaffolding signaling molecules and controlling the activity of multiple cellular enzymes. This new role of ␤-arrestins as signaling scaffolds has led to the hypothesis that they can facilitate cell migration by sequestering actin assembly activities and upstream regulators of actin assembly at the leading edge. This Minireview discusses recent advances in our understanding of how ␤-arrestin scaffolds contribute to cell migration, focusing on recently identified ␤-arrestin interacting proteins and phosphorylation targets that have known roles in actin reorganization.

β-Arrestin-Selective G Protein-Coupled Receptor Agonists Engender Unique Biological Efficacy in Vivo

“…As shown, bPTH was more effective than serum or hPTH at stimulating wild-type osteoblast migration. Consistent with the reported roles of arrestin scaffolds in GPCR-regulated actin cytoskeletal dynamics and chemotaxis (44,60,62), bPTH had no effect in ␤-arrestin2-null osteoblasts. Supportive of our functional genomic analysis of calvarial bone, these data suggest that ␤-arrestin2 plays a regulatory role in the control of preosteoblast proliferation and mediates the effects of conventional and arrestin pathway-selective PTH 1 R agonists on osteoblast survival and migration.…”

Claudin-4 is required for modulation of paracellular permeability by muscarinic acetylcholine receptor in epithelial cells

“…In the process of internalization, clathrin is first recruited to assemble at the cell membrane, then forms clathrincoated pits to move the target proteins into the cells, and finally the pits lose their coats and deliver the endocytic vesicles to the early endosome (Smythe and Ayscough, 2006). Previous studies have revealed that β-arrestin1 and β-arrestin2 have a domain that directly interacts with clathrin, and thereby triggering the endocytic events via clathrin-coated pits (Gavard and Gutkind, 2006;Min and Defea, 2011). It is noteworthy that tight junction proteins, including claudin-1, claudin-4, occludin and ZO-1, are internalized by clathrin in T84 epithelial cells (Ivanov et al, 2004).…”

“…Previous studies have revealed that β-arrestin2 has a domain that directly interacts with clathrin, thereby evoking internalization or endocytosis of target membrane proteins through the clathrindependent pathway (Gavard and Gutkind, 2006;Min and Defea, 2011). Therefore, we examined whether an interaction between claudin-4 and clathrin was induced by carbachol.…”

Genetic Deletion of β-Arrestin-2 and the Mitigation of Established Airway Hyperresponsiveness in a Murine Asthma Model

“…Thus, b-arrestins can both terminate and initiate cell signaling pathways. Importantly, barr2-dependent signaling has been shown to promote cellular chemotaxis and antiapoptosis, implicating barr2 in inflammation/metastasis (9) and propelling the investigation of its role in the study of cancer (10)(11)(12)(13)(14), atherosclerosis (15), and inflammatory disorders, including asthma.…”