How do focal adhesions disassemble?2017-12-26T14:16:20+00:00

How do focal adhesions disassemble?

Disassembly is critical during cell spreading and forward movement to allow FAs to extend outwards towards the cell periphery [1]. Disassembly of adhesions can take place as a result of retraction at the rear of the cell after adhesion maturation or at the base of protrusions during turnover. It is primarily mediated through tyrosine phosphorylation events and changes in cytoskeletal tension [2], which are controlled by regulators such as calpain [3] and microtubules [4].

Retraction-mediated disassembly is coordinated asymmetrically in order to support directional migration and usually occurs at the cell rear  (reviewed in [5]). It is associated with “sliding” of the adhesions as the edge moves inwards [6]. The sliding movement seems to be Rho/myosin II-dependent, however, the mechanism is still unclear (reviewed in [7]). A study reporting differential regulation of the turnover rates of individual plaque proteins by mechanical force [8]. This indicates that their size and molecular composition change upon variation in stress and thus could initiate FA disassembly. Large protein aggregates are known to leave the adhesion complex and disperse as they move away from the adhesion site [9]. Clusters that disperse off the sliding adhesions have been observed to move centripetally along the cell’s lateral edges, coalesce with others and can be stable over 30 min before disintegrating [6].

Microtubules (MTs) are known to negatively regulate cell contractility and hence enhance disassembly (reviewed in [10]). They have been observed to target adhesion sites [11] and eventually cause sliding or destabilization of these structures relaxation of actin bundles at the end linked to adhesion foci [12]. MTs may stimulate this highly localized event either through the tyrosine kinase Arg, which inhibits Rho [13] or via the interplay of FAK-mediated destabilization and dynamin-driven /clathrin-mediated endocytosis of integrins [14][15] (reviewed in [5]). Kinesin is also implicated in MT-regulated focal delivery of components that retard adhesion growth and promote disassembly [16]. Evidence also exists for other mechanisms for MT-mediated disassembly where MT depolymerization promotes Rho-dependent contractility by releasing bound GEF, which may cause adhesion instability [17][18].

On the other hand, at the lamellipodium-lamellum interface, turnover of nascent adhesion structures occur during migration and is dependent on the forces generated by actin depolymerization and reorganization [19][20]. Turnover of these structures has an important role in maintaining a defined lamellipodium-lamellum boundary through the protrusion/contraction cycles and actin bundling in the lamellum [21].

FAKSrc signaling pathway seems to play critical role in mediating adhesion turnover at the cell front [22][23]. It is signaled through phosphorylation of Myosin light chain kinase (MLCK) by ERK/MAP kinase, which increases actomyosin contractility [24]. Under high force, high integrin density leads to less stable integrin-ECM adhesive bonds [25]. The resulting severing of actin linkages therefore releases the receptors [6][26]. Alternately, turnover can be enhanced by FAK-mediated transient suppression of Rho activity [27][28]. Proteolysis of key adhesion components such as talin [29], β3-integrin [30] and FAK [31] by calpain is also implicated in this function.

Recycling of individual integrins through active transport to the leading edge have been shown to resensitize integrins for ligand binding [32] (reviewed in [33]). Altogether, the coordinated disassembly, recycling, and directed transport thus maintain the balance of adhesions assembly and disassembly that is required for persistent migration.

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References

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