Actin filament polymerization generates protrusive force2018-02-06T13:22:49+08:30

How does actin filament polymerization generates protrusive force?

It has been known for some time that actin polymerization produces most of the driving force for membrane protrusion [1][2][3] (reviewed in [4][5][6][7]). Experiments to identify the mechanism and minimum components for actin-based protrusion have used both pathogenic intracellular bacteria in in vitro reconstitution experiments [3] and baculovirus in host [8].

Pathogenic intracellular bacteria use mainly host-derived components to facilitate movement through (and between) cells. The bacterial ActA protein on the surface of the bacterium (e.g. Listeria monocytogenes) recruits and activates the host components needed for actin polymerization (e.g. Ena/VASP, ATP-actin). The actin filaments are assembled at the plus end nearest the bacteria membrane and the forces generated by filament assembly are translated into bacterium movement. The resulting actin comet tail is likely comprised of branched arrays of actin filaments as seen from simulation of experimental results [3, 8, 28]. The dynamics of filament assembly and turnover (and therefore bacterium motility) are controlled by capping protein, profilin, ADF/Cofilin and Arp2/3 complex.

In cells, actin filaments are initiated with their barbed ends oriented towards the plasma membrane, with ATP hydrolysis facilitating filament growth. Polymerization is favored towards the cell front and disassembly occurs more frequently at the rear (reviewed in [9]). However, only a small fraction of the overall free energy of nucleotide hydrolysis is needed to modulate G-actin monomer binding. The remaining energy is translated into a protrusive force that deforms the plasma membrane in a particular direction [10][11] [12][13] (reviewed in [5]).

The propulsive network is self-organizing and filaments with a particular orientation,with respect to the membrane, will assemble at the maximal velocity and be preferentially chosen for elongation [14]. Similarly, cell shape and migration speed is determined by a dynamic steady state that is self-organizing [15]. As actin filaments grow, they remain fixed within the cytoskeletal network (reviewed in [16]).

Factors that regulate the protrusive force of actin filaments:

Factors that influence the concentration of free G-actin (e.g. profilin [17]) or ATP-binding and hydrolysis on actin (reviewed in [8]) will promote filament assembly and membrane protrusion.

The microtubule and intermediate filament networks play a key role in regulating the global deposition pattern of the actin filaments, therefore, they will also influence membrane protrusion dynamics [18] (reviewed in [14][15][19][20][21]).

Membrane tension- In order for a cell to extend its leading edge forward, the cell must overcome resisting forces. Motile cells in living systems experience external forces from the surrounding material (usually ECM), while the major force resisting extension for cells in tissue culture are tensile forces within the plasma membrane. Biophysical models [14][22][23] (reviewed in [24][25]) and experiments with live cells have shown that the membrane extension rate is directly dependent on the membrane tension: elevated tension lowers cell membrane extension and motility, regardless of whether the tension is applied externally (e.g. stretching) or internally (e.g. contraction of stress fibers) [13][26][27].

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  1. Hill TL. Microfilament or microtubule assembly or disassembly against a force. Proc. Natl. Acad. Sci. U.S.A. 1981; 78(9):5613-7. [PMID: 6946498]
  2. Peskin CS, Odell GM, and Oster GF. Cellular motions and thermal fluctuations: the Brownian ratchet. Biophys. J. 1993; 65(1):316-24. [PMID: 8369439]
  3. Loisel TP, Boujemaa R, Pantaloni D, and Carlier MF. Reconstitution of actin-based motility of Listeria and Shigella using pure proteins. Nature 1999; 401(6753):613-6. [PMID: 10524632]
  4. Borisy GG, and Svitkina TM. Actin machinery: pushing the envelope. Curr. Opin. Cell Biol. 2000; 12(1):104-12. [PMID: 10679366]
  5. Theriot JA. The polymerization motor. Traffic 2000; 1(1):19-28. [PMID: 11208055]
  6. Pollard TD, and Borisy GG. Cellular motility driven by assembly and disassembly of actin filaments. Cell 2003; 112(4):453-65. [PMID: 12600310]
  7. Le Clainche C, and Carlier M. Regulation of actin assembly associated with protrusion and adhesion in cell migration. Physiol. Rev. 2008; 88(2):489-513. [PMID: 18391171]
  8. Ohkawa T, Volkman LE, and Welch MD. Actin-based motility drives baculovirus transit to the nucleus and cell surface. J. Cell Biol. 2010; 190(2):187-95. [PMID: 20660627]
  9. Carlier MF, and Pantaloni D. Control of actin dynamics in cell motility. J. Mol. Biol. 1997; 269(4):459-67. [PMID: 9217250]
  10. Oliver T, Dembo M, and Jacobson K. Separation of propulsive and adhesive traction stresses in locomoting keratocytes. J. Cell Biol. 1999; 145(3):589-604. [PMID: 10225959]
  11. Elson EL, Felder SF, Jay PY, Kolodney MS, and Pasternak C. Forces in cell locomotion. Biochem. Soc. Symp. 1999; 65:299-314. [PMID: 10320946]
  12. Dickinson RB, Caro L, and Purich DL. Force generation by cytoskeletal filament end-tracking proteins. Biophys. J. 2004; 87(4):2838-54. [PMID: 15454475]
  13. Marcy Y, Prost J, Carlier M, and Sykes C. Forces generated during actin-based propulsion: a direct measurement by micromanipulation. Proc. Natl. Acad. Sci. U.S.A. 2004; 101(16):5992-7. [PMID: 15079054]
  14. Mogilner A, and Oster G. Cell motility driven by actin polymerization. Biophys. J. 1996; 71(6):3030-45. [PMID: 8968574]
  15. Keren K, Pincus Z, Allen GM, Barnhart EL, Marriott G, Mogilner A, and Theriot JA. Mechanism of shape determination in motile cells. Nature 2008; 453(7194):475-80. [PMID: 18497816]
  16. Vogel V, and Sheetz M. Local force and geometry sensing regulate cell functions. Nat. Rev. Mol. Cell Biol. 2006; 7(4):265-75. [PMID: 16607289]
  17. Kang F, Purich DL, and Southwick FS. Profilin promotes barbed-end actin filament assembly without lowering the critical concentration. J. Biol. Chem. 1999; 274(52):36963-72. [PMID: 10601251]
  18. Pan Y, Jing R, Pitre A, Williams BJ, and Skalli O. Intermediate filament protein synemin contributes to the migratory properties of astrocytoma cells by influencing the dynamics of the actin cytoskeleton. FASEB J. 2008; 22(9):3196-206. [PMID: 18509200]
  19. Fuchs E, and Yang Y. Crossroads on cytoskeletal highways. Cell 1999; 98(5):547-50. [PMID: 10490093]
  20. Goode BL, Drubin DG, and Barnes G. Functional cooperation between the microtubule and actin cytoskeletons. Curr. Opin. Cell Biol. 2000; 12(1):63-71. [PMID: 10679357]
  21. Etienne-Manneville S. Actin and microtubules in cell motility: which one is in control? Traffic 2004; 5(7):470-7. [PMID: 15180824]
  22. Oster G. Biophysics of the leading lamella. Cell Motil. Cytoskeleton 1988; 10(1-2):164-71. [PMID: 3052865]
  23. Mogilner A, and Oster G. Force generation by actin polymerization II: the elastic ratchet and tethered filaments. Biophys. J. 2003; 84(3):1591-605. [PMID: 12609863]
  24. Mogilner A. On the edge: modeling protrusion. Curr. Opin. Cell Biol. 2005; 18(1):32-9. [PMID: 16318917]
  25. Rangarajan R, and Zaman MH. Modeling cell migration in 3D: Status and challenges. Cell Adh Migr 2008; 2(2):106-9. [PMID: 19262098]
  26. Sheetz MP, and Dai J. Modulation of membrane dynamics and cell motility by membrane tension. Trends Cell Biol. 1996; 6(3):85-9. [PMID: 15157483]
  27. Karl I, and Bereiter-Hahn J. Tension modulates cell surface motility: A scanning acoustic microscopy study. Cell Motil. Cytoskeleton 1999; 43(4):349-59. [PMID: 10423275]