Cytoskeleton Dynamics

How is stress fiber assembly regulated?

Tension-dependent actin polymerization and assembly of stress fibers is influenced by many factors (reviewed in [1][2]), including differences in substrate composition [3], rigidity [4][5][6] (reviewed in [7]), cell membrane phospholipids [8], external force (reviewed in [9]), as well as by strength of the connection(s) between actin filaments and the adhesion [10][11][12] (reviewed in [13][14]).

Each of these cues converges at the level of the Rho family of GTPases and their effector substrates (reviewed in [14][15][16][17]). The activity of the Rho GTPases is finely regulated by GTPase activating proteins (GAPs), guanine nucleotide exchange factors (GEFs), and guanine nucleotide dissociation inhibitors (GDIs) [18] (reviewed in [19][20]); however, actin-associated proteins such as synaptopodin can also block the degradation of RhoA and lead to stress fiber formation [21].

Stress fibers function to counter membrane tension and to keep the non-adherent regions of a cell straight [22]. Accordingly, the rate of actin assembly at the leading edge is directly dependent on the membrane tension: elevated tension lowers membrane protrusion and cell motility, regardless of whether the tension is applied externally (e.g., stretching) or internally (e.g., contraction of stress fibers) [23][24][25]. Furthermore, Rho GTPases recruit formins to initiate actin assembly from focal adhesions in a manner that is also force-dependent [17].

As tension regulates the dynamic assembly and disassembly of actin filaments [26], proteins that contribute to the structural integrity of the filaments will influence the physical transmission of forces across the network. α-actinin and filamin are enriched in arcs and stress fibers [27][28][29][30][31] and they are both known to alter the structural dynamics of the actin cytoskeleton (reviewed in [32][33]). α-actinin recruits proteins that are important for mechanosensing in stress fibers (e.g., zyxin [34][35]) and for stress fiber maintenance (e.g., CLP-36 [36], palladin [37]) whereas filamin links the filaments to cellular membranes and its degradation products may act as signaling molecules (reviewed in [33][38]). Interestingly, the association of α-actinin with actin filaments and stress fibers is highly dynamic [17][39][40] and dynamic binding is essential for proper cell function [41]; this implies that any factors that manipulate the actin-binding properties of α-actinin or its association with actin filaments (e.g., Alix [42]; RIL [43]) will likely influence the formation of stress fibers.

Membrane curvature, cross-linking and bundling of F-actin at the leading cell edge is mediated by proteins containing IM/I-BAR domains such as IRSp53 (reviewed in [44]); these proteins interact with actin-associated proteins (e.g., synaptopodin) and components of the actin polymerizing module (e.g., Mena, WAVE) to regulate the protrusive dynamics and structure of the growing actin network [45][46][47][48]. The relative expression level of IRSp53 influences stress fiber assembly: stress fibers are seen when IRSp53 levels are low, while overexpression causes their complete disassembly [49].

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 actin filament production and membrane protrusion dynamics [50] (reviewed in [51][52][53][54][55]).

References

1. Webb DJ, Parsons JT, and Horwitz AF. Adhesion assembly, disassembly and turnover in migrating cells — over and over and over again. Nat. Cell Biol. 2002; 4(4):E97-100. [PMID: 11944043]
2. 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]
3. Danen EH, Sonneveld P, Sonnenberg A, and Yamada KM. Dual stimulation of Ras/mitogen-activated protein kinase and RhoA by cell adhesion to fibronectin supports growth factor-stimulated cell cycle progression. J. Cell Biol. 2000; 151(7):1413-22. [PMID: 11134071]
4. Dubin-Thaler BJ, Giannone G, Döbereiner H, and Sheetz MP. Nanometer analysis of cell spreading on matrix-coated surfaces reveals two distinct cell states and STEPs. Biophys. J. 2004; 86(3):1794-806. [PMID: 14990505]
5. Engler AJ, Sen S, Sweeney HL, and Discher DE. Matrix elasticity directs stem cell lineage specification. Cell 2006; 126(4):677-89. [PMID: 16923388]
6. Saez A, Ghibaudo M, Buguin A, Silberzan P, and Ladoux B. Rigidity-driven growth and migration of epithelial cells on microstructured anisotropic substrates. Proc. Natl. Acad. Sci. U.S.A. 2007; 104(20):8281-6. [PMID: 17488828]
7. Discher DE, Janmey P, and Wang Y. Tissue cells feel and respond to the stiffness of their substrate. Science 2005; 310(5751):1139-43. [PMID: 16293750]
8. Fraley TS, Pereira CB, Tran TC, Singleton C, and Greenwood JA. Phosphoinositide binding regulates alpha-actinin dynamics: mechanism for modulating cytoskeletal remodeling. J. Biol. Chem. 2005; 280(15):15479-82. [PMID: 15710624]
9. Asparuhova MB, Gelman L, and Chiquet M. Role of the actin cytoskeleton in tuning cellular responses to external mechanical stress. Scand J Med Sci Sports 2009; 19(4):490-9. [PMID: 19422655]
10. Ponti A, Machacek M, Gupton SL, Waterman-Storer CM, and Danuser G. Two distinct actin networks drive the protrusion of migrating cells. Science 2004; 305(5691):1782-6. [PMID: 15375270]
11. Endlich N, Otey CA, Kriz W, and Endlich K. Movement of stress fibers away from focal adhesions identifies focal adhesions as sites of stress fiber assembly in stationary cells. Cell Motil. Cytoskeleton 2007; 64(12):966-76. [PMID: 17868136]
12. Goetz JG. Bidirectional control of the inner dynamics of focal adhesions promotes cell migration. Cell Adh Migr 2009; 3(2):185-90. [PMID: 19398887]
13. Bershadsky AD, Ballestrem C, Carramusa L, Zilberman Y, Gilquin B, Khochbin S, Alexandrova AY, Verkhovsky AB, Shemesh T, and Kozlov MM. Assembly and mechanosensory function of focal adhesions: experiments and models. Eur. J. Cell Biol. 2005; 85(3-4):165-73. [PMID: 16360240]
14. Bar-Sagi D, and Hall A. Ras and Rho GTPases: a family reunion. Cell 2000; 103(2):227-38. [PMID: 11057896]
15. Takai Y, Sasaki T, and Matozaki T. Small GTP-binding proteins. Physiol. Rev. 2001; 81(1):153-208. [PMID: 11152757]
16. Aspenström P, Fransson A, and Saras J. Rho GTPases have diverse effects on the organization of the actin filament system. Biochem. J. 2004; 377(Pt 2):327-37. [PMID: 14521508]
17. Hotulainen P, and Lappalainen P. Stress fibers are generated by two distinct actin assembly mechanisms in motile cells. J. Cell Biol. 2006; 173(3):383-94. [PMID: 16651381]
18. Olson MF, Pasteris NG, Gorski JL, and Hall A. Faciogenital dysplasia protein (FGD1) and Vav, two related proteins required for normal embryonic development, are upstream regulators of Rho GTPases. Curr. Biol. 1996; 6(12):1628-33. [PMID: 8994827]
19. Moon SY, and Zheng Y. Rho GTPase-activating proteins in cell regulation. Trends Cell Biol. 2003; 13(1):13-22. [PMID: 12480336]
20. Olofsson B. Rho guanine dissociation inhibitors: pivotal molecules in cellular signalling. Cell. Signal. 1999; 11(8):545-54. [PMID: 10433515]
21. Asanuma K, Yanagida-Asanuma E, Faul C, Tomino Y, Kim K, and Mundel P. Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Nat. Cell Biol. 2006; 8(5):485-91. [PMID: 16622418]
22. Théry M, Pépin A, Dressaire E, Chen Y, and Bornens M. Cell distribution of stress fibres in response to the geometry of the adhesive environment. Cell Motil. Cytoskeleton 2006; 63(6):341-55. [PMID: 16550544]
23. 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]
24. 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]
25. 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]
26. Hirata H, Tatsumi H, and Sokabe M. Dynamics of actin filaments during tension-dependent formation of actin bundles. Biochim. Biophys. Acta 2007; 1770(8):1115-27. [PMID: 17498881]
27. Langanger G, Moeremans M, Daneels G, Sobieszek A, De Brabander M, and De Mey J. The molecular organization of myosin in stress fibers of cultured cells. J. Cell Biol. 1986; 102(1):200-9. [PMID: 3510218]
28. Lazarides E. Immunofluorescence studies on the structure of actin filaments in tissue culture cells. J. Histochem. Cytochem. 1975; 23(7):507-28. [PMID: 1095651]
29. Sanger JW, Mittal B, and Sanger JM. Interaction of fluorescently-labeled contractile proteins with the cytoskeleton in cell models. J. Cell Biol. 1984; 99(3):918-28. [PMID: 6540785]
30. Katoh K, Masuda M, Kano Y, Jinguji Y, and Fujiwara K. Focal adhesion proteins associated with apical stress fibers of human fibroblasts. Cell Motil. Cytoskeleton 1995; 31(3):177-95. [PMID: 7585988]
31. Lee J, and Jacobson K. The composition and dynamics of cell-substratum adhesions in locomoting fish keratocytes. J. Cell. Sci. 1997; 110 ( Pt 22):2833-44. [PMID: 9427291]
32. Otey CA, and Carpen O. Alpha-actinin revisited: a fresh look at an old player. Cell Motil. Cytoskeleton 2004; 58(2):104-11. [PMID: 15083532]
33. Feng Y, and Walsh CA. The many faces of filamin: a versatile molecular scaffold for cell motility and signalling. Nat. Cell Biol. 2004; 6(11):1034-8. [PMID: 15516996]
34. Reinhard M, Zumbrunn J, Jaquemar D, Kuhn M, Walter U, and Trueb B. An alpha-actinin binding site of zyxin is essential for subcellular zyxin localization and alpha-actinin recruitment. J. Biol. Chem. 1999; 274(19):13410-8. [PMID: 10224105]
35. Colombelli J, Besser A, Kress H, Reynaud EG, Girard P, Caussinus E, Haselmann U, Small JV, Schwarz US, and Stelzer EHK. Mechanosensing in actin stress fibers revealed by a close correlation between force and protein localization. J. Cell. Sci. 2009; 122(Pt 10):1665-79. [PMID: 19401336]
36. Tamura N, Ohno K, Katayama T, Kanayama N, and Sato K. The PDZ-LIM protein CLP36 is required for actin stress fiber formation and focal adhesion assembly in BeWo cells. Biochem. Biophys. Res. Commun. 2007; 364(3):589-94. [PMID: 17964547]
37. Parast MM, and Otey CA. Characterization of palladin, a novel protein localized to stress fibers and cell adhesions. J. Cell Biol. 2000; 150(3):643-56. [PMID: 10931874]
38. Uribe R, and Jay D. A review of actin binding proteins: new perspectives. Mol. Biol. Rep. 2007; 36(1):121-5. [PMID: 17939058]
39. Edlund M, Lotano MA, and Otey CA. Dynamics of alpha-actinin in focal adhesions and stress fibers visualized with alpha-actinin-green fluorescent protein. Cell Motil. Cytoskeleton 2001; 48(3):190-200. [PMID: 11223950]
40. Goldmann WH, and Isenberg G. Analysis of filamin and alpha-actinin binding to actin by the stopped flow method. FEBS Lett. 1993; 336(3):408-10. [PMID: 8282102]
41. Bijian K, Takano T, Papillon J, Le Berre L, Michaud J, Kennedy CRJ, and Cybulsky AV. Actin cytoskeleton regulates extracellular matrix-dependent survival signals in glomerular epithelial cells. Am. J. Physiol. Renal Physiol. 2005; 289(6):F1313-23. [PMID: 16014575]
42. Pan S, Wang R, Zhou X, He G, Koomen J, Kobayashi R, Sun L, Corvera J, Gallick GE, and Kuang J. Involvement of the conserved adaptor protein Alix in actin cytoskeleton assembly. J. Biol. Chem. 2006; 281(45):34640-50. [PMID: 16966331]
43. Crockett CO, Guede-Guina F, Pugh D, Vangah-Manda M, Robinson TJ, Olubadewo JO, and Ochillo RF. Cassia alata and the preclinical search for therapeutic agents for the treatment of opportunistic infections in AIDS patients. Cell. Mol. Biol. (Noisy-le-grand) 1992; 38(7):799-802. [PMID: 1472906]
44. Ahmed S, Goh WI, and Bu W. I-BAR domains, IRSp53 and filopodium formation. Semin. Cell Dev. Biol. 2009; 21(4):350-6. [PMID: 19913105]
45. Yanagida-Asanuma E, Asanuma K, Kim K, Donnelly M, Young Choi H, Hyung Chang J, Suetsugu S, Tomino Y, Takenawa T, Faul C, and Mundel P. Synaptopodin protects against proteinuria by disrupting Cdc42:IRSp53:Mena signaling complexes in kidney podocytes. Am. J. Pathol. 2007; 171(2):415-27. [PMID: 17569780]
46. Nakagawa H, Miki H, Nozumi M, Takenawa T, Miyamoto S, Wehland J, and Small JV. IRSp53 is colocalised with WAVE2 at the tips of protruding lamellipodia and filopodia independently of Mena. J. Cell. Sci. 2003; 116(Pt 12):2577-83. [PMID: 12734400]
47. Suetsugu S, Kurisu S, Oikawa T, Yamazaki D, Oda A, and Takenawa T. Optimization of WAVE2 complex-induced actin polymerization by membrane-bound IRSp53, PIP(3), and Rac. J. Cell Biol. 2006; 173(4):571-85. [PMID: 16702231]
48. Mattila PK, Pykäläinen A, Saarikangas J, Paavilainen VO, Vihinen H, Jokitalo E, and Lappalainen P. Missing-in-metastasis and IRSp53 deform PI(4,5)P2-rich membranes by an inverse BAR domain-like mechanism. J. Cell Biol. 2007; 176(7):953-64. [PMID: 17371834]
49. Govind S, Kozma R, Monfries C, Lim L, and Ahmed S. Cdc42Hs facilitates cytoskeletal reorganization and neurite outgrowth by localizing the 58-kD insulin receptor substrate to filamentous actin. J. Cell Biol. 2001; 152(3):579-94. [PMID: 11157984]
50. 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]
51. Mogilner A, and Oster G. Cell motility driven by actin polymerization. Biophys. J. 1996; 71(6):3030-45. [PMID: 8968574]
52. 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]
53. Fuchs E, and Yang Y. Crossroads on cytoskeletal highways. Cell 1999; 98(5):547-50. [PMID: 10490093]
54. 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]
55. Etienne-Manneville S. Actin and microtubules in cell motility: which one is in control? Traffic 2004; 5(7):470-7. [PMID: 15180824]