Cytoskeleton Dynamics

What mechanisms drive retraction of the trailing edge?

Protrusion at the front and retraction at the rear are key force-generating processes at the cell periphery that culminate in the translocation of the cell. For forces to be translated into a net forward gain in cellular movement, the trailing edge must retract as the leading edge protrudes forward. In order for this to occur focal adhesions at the rear of the cell, and the actin filament network to which they are linked, must be disassembled. Prevention of this step would result in the cell being permanently anchored to its substrate.

Prior to retraction of the trailing edge, large-scale actomyosin activity at the rear of the cell reorganizes the cytoskeleton. This alters the actin flow and essentially polarizes the cell to influence the direction it will migrate [1]. The contractile forces generated by the actomyosin network facilitate the retraction of the trailing edge [2][3] via a mechanism similar to that of Myosin Motors and Actin Filament Contractions. Myosin II is a major regulator of this contractility, generating increased tensile forces at the trailing edge and simultaneously relieving tension at the leading edge [4][5]. This ultimately leads to retraction at the rear and extension at the front. Both myosin IIA and IIB are involved in this however each contributes differently. Myosin IIA is important in retraction and adhesion disassembly at the rear of the cell whilst myosin IIB plays a greater role in crosslinking of actin filaments and the establishment of a front-rear polarity [6][7].

Focal adhesion disassembly eases separation of the trailing edge from the underlying substrate in response to the increase in actomyosin contractility. The subsequent retraction of the trailing edge results from the buildup of tensile forces at the rear of the cell which sever the interactions between the cytoskeleton and the cell substrate. These interactions are maintained by integrins however during retraction the integrins will remain attached to the substrate, whilst other components of the FA move towards the cell body and dissipate [8].

Further to the intracellular processes that promote detachment, namely FA disassembly and actomyosin contractility, extracellular events are also speculated to contribute (as reviewed in [9]). Extracellular matrix (ECM) proteases could digest the underlying substrate, whilst sheddase enzymes could cleave cell surface proteins bound to the substrate. Together these intracellular and extracellular events free the trailing edge of the cell from the substrate to which it is bound, allowing retraction to occur.

References

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2. Verkhovsky AB, Svitkina TM, and Borisy GG. Network contraction model for cell translocation and retrograde flow. Biochem. Soc. Symp. 1999; 65:207-22. [PMID: 10320940]
3. Cramer LP. Molecular mechanism of actin-dependent retrograde flow in lamellipodia of motile cells. Front. Biosci. 1997; 2:d260-70. [PMID: 9206973]
4. Jay PY, Pham PA, Wong SA, and Elson EL. A mechanical function of myosin II in cell motility. J. Cell. Sci. 1995; 108 ( Pt 1):387-93. [PMID: 7738114]
5. Verkhovsky AB, Svitkina TM, and Borisy GG. Self-polarization and directional motility of cytoplasm. Curr. Biol. 1999; 9(1):11-20. [PMID: 9889119]
6. Vicente-Manzanares M, Zareno J, Whitmore L, Choi CK, and Horwitz AF. Regulation of protrusion, adhesion dynamics, and polarity by myosins IIA and IIB in migrating cells. J. Cell Biol. 2007; 176(5):573-80. [PMID: 17312025]
7. Vicente-Manzanares M, Newell-Litwa K, Bachir AI, Whitmore LA, and Horwitz AR. Myosin IIA/IIB restrict adhesive and protrusive signaling to generate front-back polarity in migrating cells. J. Cell Biol. 2011; 193(2):381-96. [PMID: 21482721]
8. Laukaitis CM, Webb DJ, Donais K, and Horwitz AF. Differential dynamics of alpha 5 integrin, paxillin, and alpha-actinin during formation and disassembly of adhesions in migrating cells. J. Cell Biol. 2001; 153(7):1427-40. [PMID: 11425873]
9. Kirfel G, Rigort A, Borm B, and Herzog V. Cell migration: mechanisms of rear detachment and the formation of migration tracks. Eur. J. Cell Biol. 2004; 83(11-12):717-24. [PMID: 15679116]