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Arrestins regulate cell spreading and motility via focal adhesion dynamics.

Cleghorn WM, Branch KM, Kook S, Arnette C, Bulus N, Zent R, Kaverina I, Gurevich EV, Weaver AM, Gurevich VV - Mol. Biol. Cell (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.

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Related in: MedlinePlus

Model of the mechanism of focal adhesion disassembly. Focal adhesions are multiprotein complexes organized around clustered active integrins that bind extracellular matrix (shown as fibronectin). FAs are connected to actin filaments and include numerous structural and signaling proteins, such as talin, vinculin, paxillin, focal adhesion kinase (FAK), and so on. FAs are very dynamic, and their disassembly is facilitated by the proximity of microtubules and triggered by clathrin-dependent internalization of integrins. Our data suggest that nonvisual arrestins, known to interact with both microtubules and clathrin, serve as a link between the two, being delivered together with associated clathrin by microtubules to FAs. The delivery of arrestin-bound clathrin to FAs facilitates integrin internalization via clathrin-coated pits (with the help of dynamin, which pinches coated vesicles off of the membrane) and thus FA disassembly.
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Figure 8: Model of the mechanism of focal adhesion disassembly. Focal adhesions are multiprotein complexes organized around clustered active integrins that bind extracellular matrix (shown as fibronectin). FAs are connected to actin filaments and include numerous structural and signaling proteins, such as talin, vinculin, paxillin, focal adhesion kinase (FAK), and so on. FAs are very dynamic, and their disassembly is facilitated by the proximity of microtubules and triggered by clathrin-dependent internalization of integrins. Our data suggest that nonvisual arrestins, known to interact with both microtubules and clathrin, serve as a link between the two, being delivered together with associated clathrin by microtubules to FAs. The delivery of arrestin-bound clathrin to FAs facilitates integrin internalization via clathrin-coated pits (with the help of dynamin, which pinches coated vesicles off of the membrane) and thus FA disassembly.

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).


Arrestins regulate cell spreading and motility via focal adhesion dynamics.

Cleghorn WM, Branch KM, Kook S, Arnette C, Bulus N, Zent R, Kaverina I, Gurevich EV, Weaver AM, Gurevich VV - Mol. Biol. Cell (2014)

Model of the mechanism of focal adhesion disassembly. Focal adhesions are multiprotein complexes organized around clustered active integrins that bind extracellular matrix (shown as fibronectin). FAs are connected to actin filaments and include numerous structural and signaling proteins, such as talin, vinculin, paxillin, focal adhesion kinase (FAK), and so on. FAs are very dynamic, and their disassembly is facilitated by the proximity of microtubules and triggered by clathrin-dependent internalization of integrins. Our data suggest that nonvisual arrestins, known to interact with both microtubules and clathrin, serve as a link between the two, being delivered together with associated clathrin by microtubules to FAs. The delivery of arrestin-bound clathrin to FAs facilitates integrin internalization via clathrin-coated pits (with the help of dynamin, which pinches coated vesicles off of the membrane) and thus FA disassembly.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 8: Model of the mechanism of focal adhesion disassembly. Focal adhesions are multiprotein complexes organized around clustered active integrins that bind extracellular matrix (shown as fibronectin). FAs are connected to actin filaments and include numerous structural and signaling proteins, such as talin, vinculin, paxillin, focal adhesion kinase (FAK), and so on. FAs are very dynamic, and their disassembly is facilitated by the proximity of microtubules and triggered by clathrin-dependent internalization of integrins. Our data suggest that nonvisual arrestins, known to interact with both microtubules and clathrin, serve as a link between the two, being delivered together with associated clathrin by microtubules to FAs. The delivery of arrestin-bound clathrin to FAs facilitates integrin internalization via clathrin-coated pits (with the help of dynamin, which pinches coated vesicles off of the membrane) and thus FA disassembly.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.

Show MeSH
Related in: MedlinePlus