Skip to main content
SpringerLink
Log in

Control of myofibroblast differentiation and function by cytoskeletal signaling

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

The cytoskeleton consists of three distinct types of protein polymer structures–microfilaments, intermediate filaments, and microtubules; each serves distinct roles in controlling cell shape, division, contraction, migration, and other processes. In addition to mechanical functions, the cytoskeleton accepts signals from outside the cell and triggers additional signals to extracellular matrix, thus playing a key role in signal transduction from extracellular stimuli through dynamic recruitment of diverse intermediates of the intracellular signaling machinery. This review summarizes current knowledge about the role of cytoskeleton in the signaling mechanism of fibroblast-to-myofibroblast differentiation–a process characterized by accumulation of contractile proteins and secretion of extracellular matrix proteins, and being critical for normal wound healing in response to tissue injury as well as for aberrant tissue remodeling in fibrotic disorders. Specifically, we discuss control of serum response factor and Hippo signaling pathways by actin and microtubule dynamics as well as regulation of collagen synthesis by intermediate filaments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CArG box:

CC(A/T)6GG DNA sequence

ECM:

extracellular matrix

ET1:

endothelin-1

GPCR:

G-protein-coupled receptors

GTPases:

guanosine triphosphate hydrolases

IDPN:

iminodipropionitrile

IF:

intermediate filaments

LPA:

lysophosphatidic acid

MRTF-A:

myocardin-related transcription factor

MT:

microtubules

RGD:

arginine/glycine/aspartate

Rho-GEFs:

Rho guanine nucleotide-exchange factors

RPEL:

arginine/proline/glutamate/leucine

S1P:

sphingosin-1-phosphate

SRF:

serum response factor

TGF-β:

transforming growth factor β

WF-A:

Withaferin A

References

  1. Gabbiani, G., Ryan, G. B., and Majne, G. (1971) Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction, Experientia, 27, 549–550.

    Article  CAS  PubMed  Google Scholar 

  2. Majno, G., Gabbiani, G., Hirschel, B. J., Ryan, G. B., and Statkov, P. R. (1971) Contraction of granulation tissue in vitro: similarity to smooth muscle, Science, 173, 548–550.

    Article  CAS  PubMed  Google Scholar 

  3. Ryan, G. B., Cliff, W. J., Gabbiani, G., Irle, C., Montandon, D., Statkov, P. R., and Majno, G. (1974) Myofibroblasts in human granulation tissue, Hum. Pathol., 5, 55–67.

    Article  CAS  PubMed  Google Scholar 

  4. Horiuchi, K., Amizuka, N., Takeshita, S., Takamatsu, H., Katsuura, M., Ozawa, H., Toyama, Y., Bonewald, L. F., and Kudo, A. (1999) Identification and characterization of a novel protein, periostin, with restricted expression to periosteum and periodontal ligament and increased expression by transforming growth factor beta, J. Bone Miner. Res., 14, 1239–1249.

    Article  CAS  PubMed  Google Scholar 

  5. Elliott, C. G., Wang, J., Guo, X., Xu, S. W., Eastwood, M., Guan, J., Leask, A., Conway, S. J., and Hamilton, D. W. (2012) Periostin modulates myofibroblast differentiation during full-thickness cutaneous wound repair, J. Cell Sci., 125, 121–132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Roberts, C. J., Birkenmeier, T. M., McQuillan, J. J., Akiyama, S. K., Yamada, S. S., Chen, W. T., Yamada, K. M., and McDonald, J. A. (1988) Transforming growth factor beta stimulates the expression of fibronectin and of both subunits of the human fibronectin receptor by cultured human lung fibroblasts, J. Biol. Chem., 263, 4586–4592.

    CAS  PubMed  Google Scholar 

  7. Serini, G., Bochaton-Piallat, M.-L., Ropraz, P., Geinoz, A., Borsi, L., Zardi, L., and Gabbiani, G. (1998) The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-β1, J. Cell Biol., 142, 873–881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Roberts, A. B., Sporn, M. B., Assoian, R. K., Smith, J. M., Roche, N. S., Wakefieldm, L. M., Heine, U. I., Liotta, L. A., Falanga, V., Kehrl, J. H., and Fauci, A. S. (1986) Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro, Proc. Natl. Acad. Sci. USA, 83, 4167–4171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Malmstrom, J., Lindberg, H., Lindberg, C., Bratt, C., Wieslander, E., Delander, E. L., Sarnstrand, B., Burns, J. S., Mose-Larsen, P., Fey, S., and Marko-Varga, G. (2004) Transforming growth factor-beta 1 specifically induce proteins involved in the myofibroblast contractile apparatus, Mol. Cell Proteomics, 3, 466–477.

    Article  PubMed  CAS  Google Scholar 

  10. Powell, D. W., Mifflin, R. C., Valentich, J. D., Crowe, S. E., Saada, J. I., and West, A. B. (1999) Myofibroblasts. I. Paracrine cells important in health and disease, Am. J. Physiol., 277, C1–C19.

    Article  CAS  PubMed  Google Scholar 

  11. Torr, E. E., Ngam, C. R., Bernau, K., TomasiniJohansson, B., Acton, B., and Sandbo, N. (2015) Myofibroblasts exhibit enhanced fibronectin assembly that is intrinsic to their contractile phenotype, J. Biol. Chem., 290, 6951–6961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang, H. Y., and Phan, S. H. (1999) Inhibition of myofibroblast apoptosis by transforming growth factor beta(1), Am. J. Resp. Cell Mol. Biol., 21, 658–665.

    Article  CAS  Google Scholar 

  13. Desmouliere, A., Chaponnier, C., and Gabbiani, G. (2005) Tissue repair, contraction, and the myofibroblast, Wound Rep. Regen., 13, 7–12.

    Article  Google Scholar 

  14. Perrin, B. J., and Ervasti, J. M. (2010) The actin gene family: function follows isoform, Cytoskeleton, 67, 630–634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Goldman, R. D., Lazarides, E., Pollack, R., and Weber, K. (1975) The distribution of actin in non-muscle cells. The use of actin antibody in the localization of actin within the microfilament bundles of mouse 3T3 cells, Exp. Cell Res., 90, 333–344.

    Article  CAS  PubMed  Google Scholar 

  16. Kreis, T. E., Winterhalter, K. H., and Birchmeier, W. (1979) In vivo distribution and turnover of fluorescently labeled actin microinjected into human fibroblasts, Proc. Natl. Acad. Sci. USA, 76, 3814–3818.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lazarides, E. (1975) Immunofluorescence studies on the structure of actin filaments in tissue culture cells, J. Histochem. Cytochem., 23, 507–528.

    Article  CAS  PubMed  Google Scholar 

  18. Lazarides, E., and Burridge, K. (1975) Alpha-actinin: immunofluorescent localization of a muscle structural protein in nonmuscle cells, Cell, 6, 289–298.

    Article  CAS  PubMed  Google Scholar 

  19. Weber, K., and Groeschel-Stewart, U. (1974) Antibody to myosin: the specific visualization of myosin-containing filaments in nonmuscle cells, Proc. Natl. Acad. Sci. USA, 71, 4561–4564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chrzanowska-Wodnicka, M., and Burridge, K. (1996) Rho-stimulated contractility drives the formation of stress fibers and focal adhesions, J. Cell Biol., 133, 1403–1415.

    Article  CAS  PubMed  Google Scholar 

  21. Paterson, H. F., Self, A. J., Garrett, M. D., Just, I., Aktories, K., and Hall, A. (1990) Microinjection of recombinant p21rho induces rapid changes in cell morphology, J. Cell Biol., 111, 1001–1007.

    Article  CAS  PubMed  Google Scholar 

  22. Giry, M., Popoff, M. R., Von Eichel-Streiber, C., and Boquet, P. (1995) Transient expression of RhoA, -B, and -C GTPases in HeLa cells potentiates resistance to Clostridium difficile toxins A and B but not to Clostridium sordellii lethal toxin, Infect. Immun., 63, 4063–4071.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ohashi, K., Nagata, K., Maekawa, M., Ishizaki, T., Narumiya, S., and Mizuno, K. (2000) Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop, J. Biol. Chem., 275, 3577–3582.

    Article  CAS  PubMed  Google Scholar 

  24. Kimura, K., Ito, M., Amano, M., Chihara, K., Fukata, Y., Nakafuku, M., Yamamori, B., Feng, J., Nakano, T., Okawa, K., Iwamatsu, A., and Kaibuchi, K. (1996) Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase), Science, 273, 245–248.

    Article  CAS  PubMed  Google Scholar 

  25. Yoneda, A., Multhauptm, H. A., and Couchman, J. R. (2005) The Rho kinases I and II regulate different aspects of myosin II activity, J. Cell Biol., 170, 443–453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lamb, N. J., Fernandez, A., Conti, M. A., Adelstein, R., Glass, D. B., Welch, W. J., and Feramisco, J. R. (1988) Regulation of actin microfilament integrity in living nonmuscle cells by the cAMP-dependent protein kinase and the myosin light chain kinase, J. Cell Biol., 106, 1955–1971.

    Article  CAS  PubMed  Google Scholar 

  27. Alberts, A. S. (2001) Identification of a carboxyl-terminal diaphanous-related formin homology protein autoregulatory domain, J. Biol. Chem., 276, 2824–2830.

    Article  CAS  PubMed  Google Scholar 

  28. Zigmond, S. H. (2004) Formin-induced nucleation of actin filaments, Curr. Opin. Cell Biol., 16, 99–105.

    Article  CAS  PubMed  Google Scholar 

  29. Hotulainen, P., and Lappalainen, P. (2006) Stress fibers are generated by two distinct actin assembly mechanisms in motile cells, J. Cell Biol., 173, 383–394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Watanabe, N., Kato, T., Fujitam, A., Ishizakim, T., and Narumiya, S. (1999) Cooperation between mDia1 and ROCK in Rho-induced actin reorganization, Nat. Cell Biol., 1, 136–143.

    Article  CAS  PubMed  Google Scholar 

  31. Farsi, J. M., and Aubin, J. E. (1984) Microfilament rearrangements during fibroblast-induced contraction of three-dimensional hydrated collagen gels, Cell Motil., 4, 29–40.

    Article  CAS  PubMed  Google Scholar 

  32. Mochitate, K., Pawelek, P., and Grinnell, F. (1991) Stress relaxation of contracted collagen gels: disruption of actin filament bundles, release of cell surface fibronectin, and down-regulation of DNA and protein synthesis, Exp. Cell Res., 193, 198–207.

    Article  CAS  PubMed  Google Scholar 

  33. Arora, P. D., Narani, N., and McCulloch, C. A. (1999) The compliance of collagen gels regulates transforming growth factor-beta induction of alpha-smooth muscle actin in fibroblasts, Am. J. Pathol., 154, 871–882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Huveneers, S., and Danen, E. H. J. (2009) Adhesion signaling–crosstalk between integrins, Src and Rho, J. Cell Sci., 122, 1059–1069.

    Article  CAS  PubMed  Google Scholar 

  35. Guilluy, C., Swaminathan, V., Garcia-Mata, R., O’Brien, E. T., Superfine, R., and Burridge, K. (2011) The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins, Nat. Cell Biol., 13, 722–727.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Desmouliere, A., Geinoz, A., Gabbiani, F., and Gabbiani, G. (1993) Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts, J. Cell Biol., 122, 103–111.

    Article  CAS  PubMed  Google Scholar 

  37. Shen, X., Li, J., Hu, P. P., Waddell, D., Zhang, J., and Wang, X. F. (2001) The activity of guanine exchange factor NET1 is essential for transforming growth factor-beta-mediated stress fiber formation, J. Biol. Chem., 276, 15362–15368.

    Article  CAS  PubMed  Google Scholar 

  38. Tsapara, A., Luthert, P., Greenwood, J., Hill, C. S., Matter, K., and Balda, M. S. (2010) The RhoA activator GEFH1/Lfc is a transforming growth factor-beta target gene and effector that regulates alpha-smooth muscle actin expression and cell migration, Mol. Biol. Cell, 21, 860–870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hinz, B., Mastrangelo, D., Iselin, C. E., Chaponnier, C., and Gabbiani, G. (2001) Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation, Am. J. Pathol., 159, 1009–1020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Delanoe-Ayari, H., Al Kurdi, R., Vallade, M., GulinoDebrac, D., and Riveline, D. (2004) Membrane and actomyosin tension promote clustering of adhesion proteins, Proc. Natl. Acad. Sci. USA, 101, 2229–2234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hinz, B., Dugina, V., Ballestrem, C., Wehrle-Haller, B., and Chaponnier, C. (2003) Alpha-smooth muscle actin is crucial for focal adhesion maturation in myofibroblasts, Mol. Biol. Cell, 14, 2508–2519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. DEl Rio, A., Perez-Jimenez, R., Liu, R., Roca-Cusachs, P., Fernandez, J. M., and Sheetz, M. P. (2009) Stretching single talin rod molecules activates vinculin binding, Science, 323, 638–641.

    Article  CAS  PubMed  Google Scholar 

  43. Sawada, Y., Tamada, M., Dubin-Thaler, B. J., Cherniavskaya, O., Sakai, R., Tanaka, S., and Sheetz, M. P. (2006) Force sensing by mechanical extension of the Src family kinase substrate p130Cas, Cell, 127, 1015–1026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bell, E., Ivarsson, B., and Merrill, C. (1979) Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro, Proc. Natl. Acad. Sci. USA, 76, 1274–1278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kolodney, M. S., and Wysolmerski, R. B. (1992) Isometric contraction by fibroblasts and endothelial cells in tissue culture: a quantitative study, J. Cell Biol., 117, 73–82.

    Article  CAS  PubMed  Google Scholar 

  46. Schwarzbauer, J. E., and De Simone, D. W. (2011) Fibronectins, their fibrillogenesis, and in vivo functions, Cold Spring Harb. Perspect. Biol., 3.

    Google Scholar 

  47. Tomasini-Johansson, B. R., Annis, D. S., and Mosher, D. F. (2006) The N-terminal 70-kDa fragment of fibronectin binds to cell surface fibronectin assembly sites in the absence of intact fibronectin, Matrix. Biol., 25, 282–293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zamir, E., Katz, B. Z., Aota, S., Yamada, K. M., Geiger, B., and Kam, Z. (1999) Molecular diversity of cell–matrix adhesions, J. Cell Sci., 112 (Pt. 11), 1655–1669.

    CAS  PubMed  Google Scholar 

  49. Baneyx, G., Baugh, L., and Vogel, V. (2002) Fibronectin extension and unfolding within cell matrix fibrils controlled by cytoskeletal tension, Proc. Natl. Acad. Sci. USA, 99, 5139–5143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhong, C., Chrzanowska-Wodnicka, M., Brown, J., Shaub, A., Belkin, A. M., and Burridge, K. (1998) Rhomediated contractility exposes a cryptic site in fibronectin and induces fibronectin matrix assembly, J. Cell Biol., 141, 539–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang, Q., Magnusson, M. K., and Mosher, D. F. (1997) Lysophosphatidic acid and microtubule-destabilizing agents stimulate fibronectin matrix assembly through Rhodependent actin stress fiber formation and cell contraction, Mol. Biol. Cell, 8, 1415–1425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wu, C., Keivens, V. M., O’Toole, T. E., McDonald, J. A., and Ginsberg, M. H. (1995) Integrin activation and cytoskeletal interaction are essential for the assembly of a fibronectin matrix, Cell, 83, 715–724.

    Article  CAS  PubMed  Google Scholar 

  53. Yoneda, A., Ushakov, D., Multhaupt, H. A., and Couchman, J. R. (2007) Fibronectin matrix assembly requires distinct contributions from Rho kinases I and -II, Mol. Biol. Cell, 18, 66–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hill, C. S., Wynne, J., and Treisman, R. (1995) The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF, Cell, 81, 1159–1170.

    Article  CAS  PubMed  Google Scholar 

  55. Sotiropoulos, A., Gineitis, D., Copeland, J., and Treisman, R. (1999) Signal-regulated activation of serum response factor is mediated by changes in actin dynamics, Cell, 98, 159–169.

    Article  CAS  PubMed  Google Scholar 

  56. Miralles, F., Posern, G., Zaromytidou, A. I., and Treisman, R. (2003) Actin dynamics control SRF activity by regulation of its coactivator MAL, Cell, 113, 329–342.

    Article  CAS  PubMed  Google Scholar 

  57. Miano, J. M. (2003) Serum response factor: toggling between disparate programs of gene expression, J. Mol. Cell. Cardiol., 35, 577–593.

    Article  CAS  PubMed  Google Scholar 

  58. Sun, Q., Chen, G., Streb, J. W., Long, X., Yang, Y., Stoeckert, C. J., Jr., and Miano, J. M. (2006) Defining the mammalian CArGome, Genome Res., 16, 197–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Esnault, C., Stewart, A., Gualdrini, F., East, P., Horswell, S., Matthews, N., and Treisman, R. (2014) Rho-actin signaling to the MRTF coactivators dominates the immediate transcriptional response to serum in fibroblasts, Genes Dev., 28, 943–958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mao, J., Yuan, H., Xie, W., Simon, M. I., and Wu, D. (1998) Specific involvement of G proteins in regulation of serum response factor-mediated gene transcription by different receptors, J. Biol. Chem., 273, 27118–27123.

    Article  CAS  PubMed  Google Scholar 

  61. Gohla, A., Offermanns, S., Wilkie, T. M., and Schultz, G. (1999) Differential involvement of Galpha12 and Galpha13 in receptor-mediated stress fiber formation, J. Biol. Chem., 274, 17901–17907.

    Article  CAS  PubMed  Google Scholar 

  62. Sandbo, N., Kregel, S., Taurin, S., Bhorade, S., and Dulin, N. O. (2009) Critical role of serum response factor in pulmonary myofibroblast differentiation induced by TGFbeta, Am. J. Respir. Cell Mol. Biol., 41, 332–338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sandbo, N., Lau, A., Kach, J., Ngam, C., Yau, D., and Dulin, N. O. (2011) Delayed stress fiber formation mediates pulmonary myofibroblast differentiation in response to TGF-beta, Am. J. Physiol., 301, L656–L666.

    CAS  Google Scholar 

  64. Cencetti, F., Bernacchioni, C., Nincheri, P., Donati, C., and Bruni, P. (2010) Transforming growth factor-beta1 induces transdifferentiation of myoblasts into myofibroblasts via up-regulation of sphingosine kinase-1/S1P3 axis, Mol. Biol. Cell, 21, 1111–1124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Small, E. M., Thatcher, J. E., Sutherland, L. B., Kinoshita, H., Gerard, R. D., Richardson, J. A., Dimaio, J. M., Sadek, H., Kuwahara, K., and Olson, E. N. (2010) Myocardin-related transcription factor-α controls myofibroblast activation and fibrosis in response to myocardial infarction, Circ. Res., 107, 294–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bernau, K., Ngam, C., Torr, E. E., Acton, B., Kach, J., Dulin, N. O., and Sandbo, N. (2015) Megakaryoblastic leukemia-1 is required for the development of bleomycininduced pulmonary fibrosis, Respir. Res., 16, 45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Zhao, X. H., Laschinger, C., Arora, P., Szaszi, K., Kapus, A., and McCulloch, C. A. (2007) Force activates smooth muscle alpha-actin promoter activity through the Rho signaling pathway, J. Cell Sci., 120, 1801–1809.

    Article  CAS  PubMed  Google Scholar 

  68. Liu, F., Mih, J. D., Shea, B. S., Kho, A. T., Sharif, A. S., Tager, A. M., and Tschumperlin, D. J. (2010) Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression, J. Cell Biol., 190, 693–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Huang, X., Yang, N., Fiore, V. F., Barker, T. H., Sun, Y., Morris, S. W., Ding, Q., Thannickal, V. J., and Zhou, Y. (2012) Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction, Am. J. Respir. Cell Mol. Biol., 47, 340–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schratt, G., Philippar, U., Hockemeyer, D., Schwarz, H., Alberti, S., and Nordheim, A. (2004) SRF regulates Bcl-2 expression and promotes cell survival during murine embryonic development, EMBO J., 23, 1834–1844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhou, Y., Huang, X., Hecker, L., Kurundkar, D., Kurundkar, A., Liu, H., Jin, T. H., Desai, L., Bernard, K., and Thannickal, V. J. (2013) Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis, J. Clin. Invest., 123, 1096–1108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sisson, T. H., Ajayi, I. O., Subbotina, N., Dodi, A. E., Rodansky, E. S., Chibucos, L. N., Kim, K. K., Keshamouni, V. G., White, E. S., Zhou, Y., Higgins, P. D., Larsen, S. D., Neubig, R. R., and Horowitz, J. C. (2015) Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis, Am. J. Pathol., 185, 969–986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Low, B. C., Pan, C. Q., Shivashankar, G. V., Bershadsky, A., Sudol, M., and Sheetz, M. (2014) YAP/TAZ as mechanosensors and mechanotransducers in regulating organ size and tumor growth, FEBS Lett., 588, 2663–2670.

    Article  CAS  PubMed  Google Scholar 

  74. Vassilev, A., Kaneko, K. J., Shu, H., Zhao, Y., and De Pamphilis, M. L. (2001) TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm, Genes Dev., 15, 1229–1241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Dupont, S., Morsut, L., Aragona, M., Enzo, E., Giulitti, S., Cordenonsi, M., Zanconato, F., Le Digabel, J., Forcato, M., Bicciato, S., Elvassore, N., and Piccolo, S. (2011) Role of YAP/TAZ in mechanotransduction, Nature, 474, 179–183.

    Article  CAS  PubMed  Google Scholar 

  76. Sansores-Garcia, L., Bossuyt, W., Wada, K., Yonemura, S., Tao, C., Sasaki, H., and Halder, G. (2011) Modulating Factin organization induces organ growth by affecting the Hippo pathway, EMBO J., 30, 2325–2335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wada, K., Itoga, K., Okano, T., Yonemura, S., and Sasaki, H. (2011) Hippo pathway regulation by cell morphology and stress fibers, Development, 138, 3907–3914.

    Article  CAS  PubMed  Google Scholar 

  78. Liu, F., Lagares, D., Choi, K. M., Stopfer, L., Marinkovic, A., Vrbanac, V., Probst, C. K., Hiemer, S. E., Sisson, T. H., Horowitz, J. C., Rosas, I. O., Fredenburgh, L. E., FeghaliBostwick, C., Varelas, X., Tager, A. M., and Tschumperlin, D. J. (2015) Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis, Am. J. Physiol., 308, L344–L357.

    Article  CAS  Google Scholar 

  79. Yu, O. M., Miyamoto, S., and Brown, J. H. (2015) Myocardin-related transcription factor A and Yes-associated protein exert dual control in G protein-coupled receptor- and RhoA-mediated transcriptional regulation and cell proliferation, Mol. Cell. Biol., 36, 39–49.

    PubMed  PubMed Central  Google Scholar 

  80. Liu, C. Y., Chan, S. W., Guo, F., Toloczko, A., Cui, L., and Hong, W. (2016) MRTF/SRF dependent transcriptional regulation of TAZ in breast cancer cells, Oncotarget, 7, 13706–13716.

    PubMed  PubMed Central  Google Scholar 

  81. Speight, P., Kofler, M., Szaszi, K., and Kapus, A. (2016) Context-dependent switch in chemo/mechanotransduction via multilevel crosstalk among cytoskeleton-regulated MRTF and TAZ and TGFbeta-regulated Smad3, Nat. Commun., 7, 11642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Desai, A., and Mitchison, T. J. (1997) Microtubule polymerization dynamics, Annu. Rev. Cell Dev. Biol., 13, 83–117.

    Article  CAS  PubMed  Google Scholar 

  83. Weisenberg, R. C., Deery, W. J., and Dickinson, P. J. (1976) Tubulin–nucleotide interactions during the polymerization and depolymerization of microtubules, Biochemistry, 15, 4248–4254.

    Article  CAS  PubMed  Google Scholar 

  84. Putnam, A. J., Schultz, K., and Mooney, D. J. (2001) Control of microtubule assembly by extracellular matrix and externally applied strain, Am. J. Physiol., 280, C556-564.

    CAS  Google Scholar 

  85. Mooney, D. J., Hansen, L. K., Langer, R., Vacanti, J. P., and Ingber, D. E. (1994) Extracellular matrix controls tubulin monomer levels in hepatocytes by regulating protein turnover, Mol. Biol. Cell, 5, 1281–1288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Heck, J. N., Ponik, S. M., Garcia-Mendoza, M. G., Pehlke, C. A., Inman, D. R., Eliceiri, K. W., and Keelym, P. J. (2012) Microtubules regulate GEF-H1 in response to extracellular matrix stiffness, Mol. Biol. Cell, 23, 2583–2592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Danowski, B. A. (1989) Fibroblast contractility and actin organization are stimulated by microtubule inhibitors, J. Cell Sci., 93 (Pt. 2), 255–266.

    CAS  PubMed  Google Scholar 

  88. Ingber, D. E., and Tensegrity, I. (2003) Cell structure and hierarchical systems biology, J. Cell Sci., 116, 1157–1173.

    Article  CAS  PubMed  Google Scholar 

  89. Krendel, M., Zenke, F. T., and Bokoch, G. M. (2002) Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton, Nat. Cell Biol., 4, 294–301.

    Article  CAS  PubMed  Google Scholar 

  90. Bartolini, F., Moseley, J. B., Schmoranzer, J., Cassimeris, L., Goode, B. L., and Gundersen, G. G. (2008) The formin mDia2 stabilizes microtubules independently of its actin nucleation activity, J. Cell Biol., 181, 523–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gaillard, J., Ramabhadran, V., Neumanne, E., Gurel, P., Blanchoin, L., Vantard, M., and Higgs, H. N. (2011) Differential interactions of the formins INF2, mDia1, and mDia2 with microtubules, Mol. Biol. Cell, 22, 4575–4587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Goode, B. L., and Eck, M. J. (2007) Mechanism and function of formins in the control of actin assembly, Annu. Rev. Biochem., 76, 593–627.

    Article  CAS  PubMed  Google Scholar 

  93. Sandbo, N., Ngam, C., Torr, E., Kregel, S., Kach, J., and Dulin, N. (2013) Control of myofibroblast differentiation by microtubule dynamics through a regulated localization of mDia2, J. Biol. Chem., 288, 15466–15473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ott, C., Iwanciw, D., Graness, A., Giehl, K., and GoppeltStruebe, M. (2003) Modulation of the expression of connective tissue growth factor by alterations of the cytoskeleton, J. Biol. Chem., 278, 44305–44311.

    Article  CAS  PubMed  Google Scholar 

  95. Samarakoon, R., Goppelt-Struebe, M., and Higgins, P. J. (2010) Linking cell structure to gene regulation: signaling events and expression controls on the model genes PAI-1 and CTGF, Cell. Signal., 22, 1413–1419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Dai, P., Nakagami, T., Tanaka, H., Hitomi, T., and Takamatsu, T. (2007) Cx43 mediates TGF-beta signaling through competitive Smads binding to microtubules, Mol. Biol. Cell, 18, 2264–2273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dong, C., Li, Z., Alvarez, R., Jr., Feng, X. H., and Clermont-Goldschmidt, P. J. (2000) Microtubule binding to Smads may regulate TGF beta activity, Mol. Cell, 5, 27–34.

    Article  CAS  PubMed  Google Scholar 

  98. Fuchs, E., and Weber, K. (1994) Intermediate filaments: structure, dynamics, function, and disease, Annu. Rev. Biochem., 63, 345–382.

    Article  CAS  PubMed  Google Scholar 

  99. Herrmann, H., Bar, H., Kreplak, L., Strelkov, S. V., and Aebi, U. (2007) Intermediate filaments: from cell architecture to nanomechanics, Nat. Rev., 8, 562–573.

    Article  CAS  Google Scholar 

  100. Gruenbaum, Y., Margalit, A., Goldman, R. D., Shumaker, D. K., and Wilson, K. L. (2005) The nuclear lamina comes of age, Nat. Rev., 6, 21–31.

    Article  CAS  Google Scholar 

  101. Goldman, R. D., Khuon, S., Chou, Y. H., Opal, P., and Steinert, P. M. (1996) The function of intermediate filaments in cell shape and cytoskeletal integrity, J. Cell Biol., 134, 971–983.

    Article  CAS  PubMed  Google Scholar 

  102. Parry, D. A., and Steinert, P. M. (1999) Intermediate filaments: molecular architecture, assembly, dynamics and polymorphism, Quart. Rev. Biophys., 32, 99–187.

    Article  CAS  Google Scholar 

  103. Colucci-Guyon, E., Portier, M. M., Dunia, I., Paulin, D., Pournin, S., and Babinet, C. (1994) Mice lacking vimentin develop and reproduce without an obvious phenotype, Cell, 79, 679–694.

    Article  CAS  PubMed  Google Scholar 

  104. Eckes, B., Colucci-Guyon, E., Smola, H., Nodder, S., Babinet, C., Krieg, T., and Martin, P. (2000) Impaired wound healing in embryonic and adult mice lacking vimentin, J. Cell Sci., 113 (Pt. 13), 2455–2462.

    CAS  PubMed  Google Scholar 

  105. Mor-Vaknin, N., Legendre, M., Yu, Y., Serezani, C. H., Garg, S. K., Jatzek, A., Swanson, M. D., GonzalezHernandez, M. J., Teitz-Tennenbaum, S., Punturieri, A., Engleberg, N. C., Banerjee, R., Peters-Golden, M., Kao, J. Y., and Markovitz, D. M. (2013) Murine colitis is mediated by vimentin, Sci. Rep., 3, 1045.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Dos Santos, G., Rogel, M. R., Baker, M. A., Troken, J. R., Urich, D., Morales-Nebreda, L., Sennello, J. A., Kutuzov, M. A., Sitikov, A., Davis, J. M., Lam, A. P., Cheresh, P., Kamp, D., Shumaker, D. K., Budinger, G. R., and Ridge, K. M. (2015) Vimentin regulates activation of the NLRP3 inflammasome, Nat. Commun., 6, 6574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Eckes, B., Dogic, D., Colucci-Guyon, E., Wang, N., Maniotis, A., Ingber, D., Merckling, A., Langa, F., Aumailley, M., Delouvee, A., Koteliansky, V., Babinet, C., and Krieg, T. (1998) Impaired mechanical stability, migration and contractile capacity in vimentin-deficient fibroblasts, J. Cell Sci., 111 (Pt. 13), 1897–1907.

    CAS  PubMed  Google Scholar 

  108. Challa, A. A., and Stefanovic, B. (2011) A novel role of vimentin filaments: binding and stabilization of collagen mRNAs, Mol. Cell. Biol., 31, 3773–3789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Krupsky, M., Kuang, P. P., and Goldstein, R. H. (1997) Regulation of type I collagen mRNA by amino acid deprivation in human lung fibroblasts, J. Biol. Chem., 272, 13864–13868.

    Article  CAS  PubMed  Google Scholar 

  110. Ricupero, D. A., Poliks, C. F., Rishikof, D. C., Cuttle, K. A., Kuang, P. P., and Goldstein, R. H. (2001) Phosphatidylinositol 3-kinase-dependent stabilization of alpha1(I) collagen mRNA in human lung fibroblasts, Am. J. Physiol., 281, C99–C105.

    CAS  Google Scholar 

  111. Rishikof, D. C., Kuang, P. P., Poliks, C., and Goldstein, R. H. (1998) Regulation of type I collagen mRNA in lung fibroblasts by cystine availability, Biochem. J., 331 (Pt. 2), 417–422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Cai, L., Fritz, D., Stefanovic, L., and Stefanovic, B. (2010) Binding of LARP6 to the conserved 5′ stem-loop regulates translation of mRNAs encoding type I collagen, J. Mol. Biol., 395, 309–326.

    Article  CAS  PubMed  Google Scholar 

  113. Challa, A. A., Vukmirovic, M., Blackmon, J., and Stefanovic, B. (2012) Withaferin-A reduces type I collagen expression in vitro and inhibits development of myocardial fibrosis in vivo, PloS One, 7, e42989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Bargagna-Mohan, P., Hamza, A., Kim, Y. E., Khuan Abby Ho, Y., Mor-Vaknin, N., Wendschlag, N., Liu, J., Evans, R. M., Markovitz, D. M., Zhan, C. G., Kim, K. B., and Mohan, R. (2007) The tumor inhibitor and antiangiogenic agent Withaferin A targets the intermediate filament protein vimentin, Chem. Biol., 14, 623–634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Zhang, Y., and Stefanovic, B. (2016) Akt mediated phosphorylation of LARP6; critical step in biosynthesis of type I collagen, Sci. Rep., 6, 22597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Wisconsin, Department of Medicine, Madison, WI, USA

    N. Sandbo

  2. Lomonosov Moscow State University, Faculty of Biology, Laboratory of Biomembranes, 119991, Moscow, Russia

    L. V. Smolyaninova & S. N. Orlov

  3. Siberian State Medical University, 634050, Tomsk, Russia

    S. N. Orlov & N. O. Dulin

  4. University of Chicago, Department of Medicine, Madison, IL, 5841, USA

    N. O. Dulin

Authors
  1. N. Sandbo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. V. Smolyaninova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. N. Orlov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. O. Dulin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to S. N. Orlov or N. O. Dulin.

Additional information

Original Russian Text © N. Sandbo, L. V. Smolyaninova, S. N. Orlov, N. O. Dulin, 2016, published in Uspekhi Biologicheskoi Khimii, 2016, Vol. 56, pp. 259–282.

These authors contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sandbo, N., Smolyaninova, L.V., Orlov, S.N. et al. Control of myofibroblast differentiation and function by cytoskeletal signaling. Biochemistry Moscow 81, 1698–1708 (2016). https://doi.org/10.1134/S0006297916130071

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297916130071

Keywords

Search

Navigation