Arrestins regulate cell spreading and motility via focal adhesion dynamics.
Bottom Line: Clathrin exhibited decreased dynamics near FA in arrestin-deficient cells.In contrast to wild-type arrestins, mutants deficient in clathrin binding did not rescue the phenotype.Collectively the data indicate that arrestins are key regulators of FA disassembly linking microtubules and clathrin.
Affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.Show MeSH
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Mentions: On GPCR binding, arrestins undergo a distinct conformational change (Gurevich and Gurevich, 2004) that exposes binding sites for AP2 and clathrin (Gurevich and Gurevich, 2003) to initiate receptor endocytosis. Arrestins bind microtubules via the same interface as GPCRs (Hanson et al., 2007). Although the conformations of GPCR- and microtubule-bound arrestins differ (Hanson et al., 2006), AP2- and clathrin-binding sites are exposed in both cases by virtue of similar release of the arrestin C-tail (Hanson et al., 2006, 2007). Thus it is entirely possible that arrestins provide the link between microtubules and integrin endocytosis by recruiting clathrin to FAs, thereby promoting integrin internalization. Our data strongly suggest that this is the case: arrestin mutants that do not bind clathrin fail to rescue the DKO phenotype (Figure 6), suggesting that the ability of arrestins to regulate FA disassembly is dependent on their interaction with clathrin. In addition, clathrin dynamics near FAs is also impaired in the absence of arrestins, and clathrin association with microtubules is severely reduced in DKO cells (Figure 7). Collectively these data suggest that the role of arrestins in FA disassembly is to link microtubules and clathrin, which is essential for endocytic machinery to be properly targeted to FAs to internalize integrin (Figure 8).
Affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.