Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Linking actin dynamics and gene transcription to drive cellular motile functions

Nature Reviews Molecular Cell Biology volume 11, pages 353–365 (2010)Cite this article

Subjects

Key Points

  • Numerous cell surface receptors modulate cellular motile functions through the control of dynamic actin polymerization. The status of cytoplasmic actin is sensed and communicated to the nucleus in order to elicit required changes in gene expression.

  • The status of cytoskeletal actin dynamics is communicated to the nucleus by the shuttling of globular actin (G-actin)- and filamentous actin (F-actin)-binding proteins (G-ABPs and F-ABPs, respectively). Cytoskeletal F-actin complexes are often associated with additional proteins (F-ACAPs), which can also translocate to the nucleus.

  • Myocardin-related transcription factors (MRTFs) are cofactors of the transcription factor serum response factor (SRF). MRTFs bind cytoplasmic G-actin and are released to translocate to the nucleus on stimulation of actin polymerization.

  • The nuclear activity of MRTFs is subject to regulation by nuclear G-actin. G-actin regulates activity of the MRTF–SRF complex and the nuclear export of MRTF.

  • The actin–MRTF–SRF circuit controls the expression of target genes that encode structural and regulatory components of the actin cytoskeleton. Thereby, positive and negative feedback loops can be activated to control cell motility by regulating actin dynamics.

  • In addition to regulating the expression of cytoskeletal genes, SRF and members of the myocardin family regulate the expression of microRNAs, which provide additional feedback loops to modulate SRF signalling, cytoskeletal function and muscle development.

  • Abnormalities in actin signalling mediated by the MRTF–SRF circuit are thought to have a key role in various diseases, including cancer, heart disease and vascular disorders.

Abstract

Numerous physiological and pathological stimuli promote the rearrangement of the actin cytoskeleton, thereby modulating cellular motile functions. Although it seems intuitively obvious that cell motility requires coordinated protein biosynthesis, until recently the linkage between cytoskeletal actin dynamics and correlated gene activities remained unknown. This knowledge gap was filled in part by the discovery that globular actin polymerization liberates myocardin-related transcription factor (MRTF) cofactors, thereby inducing the nuclear transcription factor serum response factor (SRF) to modulate the expression of genes encoding structural and regulatory effectors of actin dynamics. This insight stimulated research to better understand the actin–MRTF–SRF circuit and to identify alternative mechanisms that link cytoskeletal dynamics and genome activity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Receptors affecting actin dynamics and MRTF-mediated regulation of SRF target genes.
Figure 2: Actin-binding proteins as microfilament messengers.
Figure 3: Structure of myocardin family members.
Figure 4: SRF-mediated regulation of miRNAs.

Similar content being viewed by others

References

  1. Le Clainche, C. & Carlier, M. F. Regulation of actin assembly associated with protrusion and adhesion in cell migration. Physiol. Rev. 88, 489–513 (2008).

    CAS  PubMed  Google Scholar 

  2. Jaffe, A. B. & Hall, A. Rho GTPases: biochemistry and biology. Annu. Rev. Cell Dev. Biol. 21, 247–269 (2005).

    CAS  PubMed  Google Scholar 

  3. Pollard, T. D. Regulation of actin filament assembly by Arp2/3 complex and formins. Annu. Rev. Biophys. Biomol. Struct. 36, 451–477 (2007).

    CAS  PubMed  Google Scholar 

  4. Allingham, J. S., Klenchin, V. A. & Rayment, I. Actin-targeting natural products: structures, properties and mechanisms of action. Cell. Mol. Life Sci. 63, 2119–2134 (2006).

    CAS  PubMed  Google Scholar 

  5. Cotton, M. & Claing, A. G protein-coupled receptors stimulation and the control of cell migration. Cell. Signal. 21, 1045–1053 (2009).

    CAS  PubMed  Google Scholar 

  6. Iguchi, T. et al. Orphan G protein-coupled receptor GPR56 regulates neural progenitor cell migration via a Gα12/13 and Rho pathway. J. Biol. Chem. 283, 14469–14478 (2008).

    CAS  PubMed  Google Scholar 

  7. Descot, A. et al. Negative regulation of the EGFR-MAPK cascade by actin-MAL-mediated Mig6/Errfi-1 induction. Mol. Cell 35, 291–304 (2009).

    CAS  PubMed  Google Scholar 

  8. Lockman, K. et al. Sphingosine 1-phosphate stimulates smooth muscle cell differentiation and proliferation by activating separate serum response factor co-factors. J. Biol. Chem. 279, 42422–42430 (2004).

    CAS  PubMed  Google Scholar 

  9. Schiller, M. R. Coupling receptor tyrosine kinases to Rho GTPases — GEFs what's the link. Cell. Signal. 18, 1834–1843 (2006).

    CAS  PubMed  Google Scholar 

  10. Chai, J., Jones, M. K. & Tarnawski, A. S. Serum response factor is a critical requirement for VEGF signaling in endothelial cells and VEGF-induced angiogenesis. Faseb J. 18, 1264–1266 (2004).

    CAS  PubMed  Google Scholar 

  11. Knoll, B. et al. Serum response factor controls neuronal circuit assembly in the hippocampus. Nature Neurosci. 9, 195–204 (2006). This paper shows for the first time the essential role of SRF-controlled actin dynamics for the regulation of mouse neuronal development, neurite outgrowth and axonal guidance. See also references 12 and 13.

    PubMed  Google Scholar 

  12. Stern, S. et al. A nuclear actin function regulates neuronal motility by serum response factor-dependent gene transcription. J. Neurosci. 29, 4512–4518 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wickramasinghe, S. R. et al. Serum response factor mediates NGF-dependent target innervation by embryonic DRG sensory neurons. Neuron 58, 532–545 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Franco, C. A. et al. Serum response factor is required for sprouting angiogenesis and vascular integrity. Dev. Cell 15, 448–461 (2008).

    CAS  PubMed  Google Scholar 

  15. Holtz, M. L. & Misra, R. P. Endothelial-specific ablation of serum response factor causes hemorrhaging, yolk sac vascular failure, and embryonic lethality. BMC Dev. Biol. 8, 65–78 (2008).

    PubMed  PubMed Central  Google Scholar 

  16. Knoll, B. & Nordheim, A. Functional versatility of transcription factors in the nervous system: the SRF paradigm. Trends Neurosci. 32, 432–442 (2009).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  18. Zhao, X. H. et al. Force activates smooth muscle α-actin promoter activity through the Rho signaling pathway. J. Cell Sci. 120, 1801–1809 (2007).

    CAS  PubMed  Google Scholar 

  19. Moustakas, A. & Heldin, C. H. Dynamic control of TGF-β signaling and its links to the cytoskeleton. FEBS Lett. 582, 2051–2065 (2008).

    CAS  PubMed  Google Scholar 

  20. Fan, L. et al. Cell contact-dependent regulation of epithelial-myofibroblast transition via the Rho–Rho kinase–phospho-myosin pathway. Mol. Biol. Cell 18, 1083–1097 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hinson, J. S., Medlin, M. D., Lockman, K., Taylor, J. M. & Mack, C. P. Smooth muscle cell-specific transcription is regulated by nuclear localization of the myocardin-related transcription factors. Am. J. Physiol. Heart Circ. Physiol. 292, H1170–H1180 (2007).

    CAS  PubMed  Google Scholar 

  22. Morita, T., Mayanagi, T. & Sobue, K. Dual roles of myocardin-related transcription factors in epithelial mesenchymal transition via slug induction and actin remodeling. J. Cell Biol. 179, 1027–1042 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Lagna, G. et al. Control of phenotypic plasticity of smooth muscle cells by bone morphogenetic protein signaling through the myocardin-related transcription factors. J. Biol. Chem. 282, 37244–37255 (2007).

    CAS  PubMed  Google Scholar 

  24. Busche, S., Descot, A., Julien, S., Genth, H. & Posern, G. Epithelial cell-cell contacts regulate SRF-mediated transcription via Rac-actin-MAL signalling. J. Cell Sci. 121, 1025–1035 (2008).

    CAS  PubMed  Google Scholar 

  25. Sebe, A. et al. Rac, PAK and p38 regulate cell contact-dependent nuclear translocation of myocardin-related transcription factor. FEBS Lett. 582, 291–298 (2008).

    CAS  PubMed  Google Scholar 

  26. Perez-Moreno, M. & Fuchs, E. Catenins: keeping cells from getting their signals crossed. Dev. Cell 11, 601–612 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Winter, C. G. et al. Drosophila Rho-associated kinase (Drok) links Frizzled-mediated planar cell polarity signaling to the actin cytoskeleton. Cell 105, 81–91 (2001).

    CAS  PubMed  Google Scholar 

  28. Lai, S. L., Chien, A. J. & Moon, R. T. Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis. Cell Res. 19, 532–545 (2009).

    CAS  PubMed  Google Scholar 

  29. Simons, M. & Mlodzik, M. Planar cell polarity signaling: from fly development to human disease. Annu. Rev. Genet. 42, 517–540 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Roszko, I., Sawada, A. & Solnica-Krezel, L. Regulation of convergence and extension movements during vertebrate gastrulation by the Wnt/PCP pathway. Semin. Cell Dev. Biol. 20, 986–997 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Gieni, R. S. & Hendzel, M. J. Actin dynamics and functions in the interphase nucleus: moving toward an understanding of nuclear polymeric actin. Biochem. Cell Biol. 87, 283–306 (2009).

    CAS  PubMed  Google Scholar 

  32. Zheng, B., Han, M., Bernier, M. & Wen, J. K. Nuclear actin and actin-binding proteins in the regulation of transcription and gene expression. FEBS J. 276, 2669–26685 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Coso, O. A. et al. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 81, 1137–1146 (1995).

    CAS  PubMed  Google Scholar 

  34. Minden, A., Lin, A., Claret, F. X., Abo, A. & Karin, M. Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell 81, 1147–1157 (1995).

    CAS  PubMed  Google Scholar 

  35. Rosso, S. B., Sussman, D., Wynshaw-Boris, A. & Salinas, P. C. Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nature Neurosci. 8, 34–42 (2005).

    CAS  PubMed  Google Scholar 

  36. Teramoto, H. et al. Signaling from the small GTP-binding proteins Rac1 and Cdc42 to the c-Jun N-terminal kinase/stress-activated protein kinase pathway. A role for mixed lineage kinase 3/protein-tyrosine kinase 1, a novel member of the mixed lineage kinase family. J. Biol. Chem. 271, 27225–27228 (1996).

    CAS  PubMed  Google Scholar 

  37. Marinissen, M. J. et al. The small GTP-binding protein RhoA regulates c-Jun by a ROCK-JNK signaling axis. Mol. Cell 14, 29–41 (2004).

    CAS  PubMed  Google Scholar 

  38. Girardin, S. E. & Yaniv, M. A direct interaction between JNK1 and CrkII is critical for Rac1-induced JNK activation. EMBO J. 20, 3437–3446 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Fazal, F. et al. Essential role of cofilin-1 in regulating thrombin-induced RelA/p65 nuclear translocation and intercellular adhesion molecule 1 (ICAM-1) expression in endothelial cells. J. Biol. Chem. 284, 21047–21056 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Cowell, C. F. et al. Loss of cell-cell contacts induces NF-κB via RhoA-mediated activation of protein kinase D1. J. Cell Biochem. 106, 714–728 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Coutts, A. S., Weston, L. & La Thangue, N. B. A transcription co-factor integrates cell adhesion and motility with the p53 response. Proc. Natl Acad. Sci. USA 106, 19872–19877 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Zuchero, J. B., Coutts, A. S., Quinlan, M. E., Thangue, N. B. & Mullins, R. D. p53-cofactor JMY is a multifunctional actin nucleation factor. Nature Cell Biol. 11, 451–459 (2009).

    CAS  PubMed  Google Scholar 

  43. Kremer, B. E., Adang, L. A. & Macara, I. G. Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7. Cell 130, 837–850 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Hervy, M., Hoffman, L. & Beckerle, M. C. From the membrane to the nucleus and back again: bifunctional focal adhesion proteins. Curr. Opin. Cell Biol. 18, 524–532 (2006).

    CAS  PubMed  Google Scholar 

  45. Kadrmas, J. L. & Beckerle, M. C. The LIM domain: from the cytoskeleton to the nucleus. Nature Rev. Mol. Cell Biol. 5, 920–931 (2004).

    CAS  Google Scholar 

  46. Chang, D. F. et al. Cysteine-rich LIM-only proteins CRP1 and CRP2 are potent smooth muscle differentiation cofactors. Dev. Cell 4, 107–118 (2003).

    CAS  PubMed  Google Scholar 

  47. Philippar, U. et al. The SRF target gene Fhl2 antagonizes RhoA/MAL-dependent activation of SRF. Mol. Cell 16, 867–880 (2004).

    CAS  PubMed  Google Scholar 

  48. Schratt, G. et al. Serum response factor is crucial for actin cytoskeletal organization and focal adhesion assembly in embryonic stem cells. J. Cell Biol. 156, 737–750 (2002). Using SRF-deficient embryonic stem cells, this paper uncovers the essential function of SRF in the control of actin cytoskeletal assembly, cell migration and cell adhesion.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Hill, C. S., Wynne, J. & Treisman, R. The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. Cell 81, 1159–1170 (1995). This paper describes for the first time that SRF is a nuclear target of Rho-mediated signalling.

    CAS  PubMed  Google Scholar 

  50. Posern, G., Sotiropoulos, A. & Treisman, R. Mutant actins demonstrate a role for unpolymerized actin in control of transcription by serum response factor. Mol. Biol. Cell 13, 4167–4178 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sotiropoulos, A., Gineitis, D., Copeland, J. & Treisman, R. Signal-regulated activation of serum response factor is mediated by changes in actin dynamics. Cell 98, 159–169 (1999). This paper reveals the regulation of SRF activity by G-actin and actin dynamics, consistent with the subsequent discovery that MRTFs are a key intermediary between actin dynamics and SRF activation. See also references 50, 74 and 75.

    CAS  PubMed  Google Scholar 

  52. Miralles, F., Posern, G., Zaromytidou, A. I. & Treisman, R. Actin dynamics control SRF activity by regulation of its coactivator MAL. Cell 113, 329–342 (2003). This important paper shows that MRTF-A binds monomeric G-actin in the cytoplasm through the N-terminal RPEL motifs and translocates to the nucleus to interact with SRF in response to actin polymerization. See also reference 128.

    CAS  PubMed  Google Scholar 

  53. Norman, C., Runswick, M., Pollock, R. & Treisman, R. Isolation and properties of cDNA clones encoding SRF, a transcription factor that binds to the c-Fos serum response element. Cell 55, 989–1003 (1988). This paper describes the initial cloning of SRF and its mechanism of action as a dimeric transcriptional activator through binding to the CArG box DNA motif.

    CAS  PubMed  Google Scholar 

  54. Shore, P. & Sharrocks, A. D. The MADS-box family of transcription factors. Eur. J. Biochem. 229, 1–13 (1995).

    CAS  PubMed  Google Scholar 

  55. Pellegrini, L., Tan, S. & Richmond, T. J. Structure of serum response factor core bound to DNA. Nature 376, 490–498 (1995).

    CAS  PubMed  Google Scholar 

  56. Treisman, R. Identification of a protein-binding site that mediates transcriptional response of the c-fos gene to serum factors. Cell 46, 567–574 (1986). This report describes for the first time the binding of a transcription factor, later identified as SRF (see reference 53), to the c-fos transcriptional regulatory element termed SRE.

    CAS  PubMed  Google Scholar 

  57. Miano, J. M., Long, X. & Fujiwara, K. Serum response factor: master regulator of the actin cytoskeleton and contractile apparatus. Am. J. Physiol. Cell Physiol. 292, C70–C81 (2007).

    CAS  PubMed  Google Scholar 

  58. Posern, G. & Treisman, R. Actin' together: serum response factor, its cofactors and the link to signal transduction. Trends Cell Biol. 16, 588–596 (2006).

    CAS  PubMed  Google Scholar 

  59. Selvaraj, A. & Prywes, R. Expression profiling of serum inducible genes identifies a subset of SRF target genes that are MKL dependent. BMC Mol. Biol. 5, 13–28 (2004).

    PubMed  PubMed Central  Google Scholar 

  60. Sun, Q. et al. Defining the mammalian CArGome. Genome Res. 16, 197–207 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Stritt, C. et al. Paracrine control of oligodendrocyte differentiation by SRF-directed neuronal gene expression. Nature Neurosci. 12, 418–427 (2009).

    CAS  PubMed  Google Scholar 

  62. Shaw, P. E., Schroter, H. & Nordheim, A. The ability of a ternary complex to form over the serum response element correlates with serum inducibility of the human c-Fos promoter. Cell 56, 563–572 (1989). This is the first report of SRF recruiting a cofactor (named TCF) to regulate target gene activity.

    CAS  PubMed  Google Scholar 

  63. Buchwalter, G., Gross, C. & Wasylyk, B. Ets ternary complex transcription factors. Gene 324, 1–14 (2004).

    CAS  PubMed  Google Scholar 

  64. Dalton, S. & Treisman, R. Characterization of SAP-1, a protein recruited by serum response factor to the c-Fos serum response element. Cell 68, 597–612 (1992).

    CAS  PubMed  Google Scholar 

  65. Hipskind, R. A., Rao, V. N., Mueller, C. G., Reddy, E. S. & Nordheim, A. Ets-related protein Elk-1 is homologous to the c-Fos regulatory factor p62TCF. Nature 354, 531–534 (1991).

    CAS  PubMed  Google Scholar 

  66. Parmacek, M. S. Myocardin-related transcription factors: critical coactivators regulating cardiovascular development and adaptation. Circ. Res. 100, 633–644 (2007).

    CAS  PubMed  Google Scholar 

  67. Pipes, G. C., Creemers, E. E. & Olson, E. N. The myocardin family of transcriptional coactivators: versatile regulators of cell growth, migration, and myogenesis. Genes Dev. 20, 1545–1556 (2006).

    CAS  PubMed  Google Scholar 

  68. Wang, D. et al. Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell 105, 851–862 (2001). This important paper reports the discovery of myocardin, the founding member of the myocardin family of co-activators and a powerful activator of SRF-dependent transcription in cardiac muscle cells.

    CAS  PubMed  Google Scholar 

  69. Wang, D. Z. et al. Potentiation of serum response factor activity by a family of myocardin-related transcription factors. Proc. Natl Acad. Sci. USA 99, 14855–14860 (2002). This paper reports the identification, structure, function and expression of MRTF-A and MRTF-B, showing their ability to act as potent co-activators of SRF.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Gineitis, D. & Treisman, R. Differential usage of signal transduction pathways defines two types of serum response factor target gene. J. Biol. Chem. 276, 24531–24539 (2001).

    CAS  PubMed  Google Scholar 

  71. Wang, Z. et al. Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression. Nature 428, 185–189 (2004).

    CAS  PubMed  Google Scholar 

  72. Zaromytidou, A. I., Miralles, F. & Treisman, R. MAL and ternary complex factor use different mechanisms to contact a common surface on the serum response factor DNA-binding domain. Mol. Cell. Biol. 26, 4134–4148 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Arsenian, S., Weinhold, B., Oelgeschlager, M., Ruther, U. & Nordheim, A. Serum response factor is essential for mesoderm formation during mouse embryogenesis. EMBO J. 17, 6289–6299 (1998). Through the creation of SRF-deficient embryos, this paper shows for the first time that SRF is essential for mesoderm formation during embryogenesis, probably reflecting in part its requisite role for the activation of cytoskeletal gene expression and cell migration.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Guettler, S., Vartiainen, M. K., Miralles, F., Larijani, B. & Treisman, R. RPEL motifs link the serum response factor cofactor MAL but not myocardin to Rho signaling via actin binding. Mol. Cell. Biol. 28, 732–742 (2008).

    CAS  PubMed  Google Scholar 

  75. Posern, G., Miralles, F., Guettler, S. & Treisman, R. Mutant actins that stabilise F-actin use distinct mechanisms to activate the SRF coactivator MAL. EMBO J. 23, 3973–3983 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Vartiainen, M. K., Guettler, S., Larijani, B. & Treisman, R. Nuclear actin regulates dynamic subcellular localization and activity of the SRF cofactor MAL. Science 316, 1749–1752 (2007). This manuscript describes a role for nuclear G-actin in regulating the activity of nuclear MRTF.

    CAS  PubMed  Google Scholar 

  77. Mouilleron, S., Guettler, S., Langer, C. A., Treisman, R. & McDonald, N. Q. Molecular basis for G-actin binding to RPEL motifs from the serum response factor coactivator MAL. EMBO J. 27, 3198–3208 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Kuwahara, K., Barrientos, T., Pipes, G. C., Li, S. & Olson, E. N. Muscle-specific signaling mechanism that links actin dynamics to serum response factor. Mol. Cell. Biol. 25, 3173–3181 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang, Z., Wang, D. Z., Pipes, G. C. & Olson, E. N. Myocardin is a master regulator of smooth muscle gene expression. Proc. Natl Acad. Sci. USA 100, 7129–7134 (2003). This paper shows that myocardin acts as a master regulator of smooth muscle gene expression and can reprogramme fibroblasts to adopt a smooth muscle fate. See also references 104–106.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Huang, J. et al. Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice. J. Clin. Invest. 118, 515–525 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Huang, J. et al. Myocardin is required for cardiomyocyte survival and maintenance of heart function. Proc. Natl Acad. Sci. USA 106, 18734–18739 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Li, S., Wang, D. Z., Wang, Z., Richardson, J. A. & Olson, E. N. The serum response factor coactivator myocardin is required for vascular smooth muscle development. Proc. Natl Acad. Sci. USA 100, 9366–9370 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Sun, Y. et al. Acute myeloid leukemia-associated Mkl1 (Mrtf-a) is a key regulator of mammary gland function. Mol. Cell. Biol. 26, 5809–5826 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Li, S., Chang, S., Qi, X., Richardson, J. A. & Olson, E. N. Requirement of a myocardin-related transcription factor for development of mammary myoepithelial cells. Mol. Cell. Biol. 26, 5797–5808 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Oh, J., Richardson, J. A. & Olson, E. N. Requirement of myocardin-related transcription factor-B for remodeling of branchial arch arteries and smooth muscle differentiation. Proc. Natl Acad. Sci. USA 102, 15122–15127 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Muehlich, S. et al. Serum-induced phosphorylation of the serum response factor coactivator MKL1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. Mol. Cell. Biol. 28, 6302–6313 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Kalita, K., Kharebava, G., Zheng, J. J. & Hetman, M. Role of megakaryoblastic acute leukemia-1 in ERK1/2-dependent stimulation of serum response factor-driven transcription by BDNF or increased synaptic activity. J. Neurosci. 26, 10020–10032 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Kuwahara, K. et al. Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity. J. Clin. Invest. 117, 1324–1334 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Chen, C. Y. & Schwartz, R. J. Recruitment of the tinman homolog Nkx-2.5 by serum response factor activates cardiac α-actin gene transcription. Mol. Cell. Biol. 16, 6372–6384 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Belaguli, N. S. et al. Cardiac tissue enriched factors serum response factor and GATA-4 are mutual coregulators. Mol. Cell. Biol. 20, 7550–7558 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Sepulveda, J. L., Vlahopoulos, S., Iyer, D., Belaguli, N. & Schwartz, R. J. Combinatorial expression of GATA4, Nkx2–5, and serum response factor directs early cardiac gene activity. J. Biol. Chem. 277, 25775–25782 (2002).

    CAS  PubMed  Google Scholar 

  92. Neuman, N. A. et al. The four-and-a-half LIM domain protein 2 regulates vascular smooth muscle phenotype and vascular tone. J. Biol. Chem. 284, 13202–13212 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Davis, F. J., Gupta, M., Camoretti-Mercado, B., Schwartz, R. J. & Gupta, M. P. Calcium/calmodulin-dependent protein kinase activates serum response factor transcription activity by its dissociation from histone deacetylase, HDAC4. Implications in cardiac muscle gene regulation during hypertrophy. J. Biol. Chem. 278, 20047–20058 (2003).

    CAS  PubMed  Google Scholar 

  94. Hayashi, K., Nakamura, S., Nishida, W. & Sobue, K. Bone morphogenetic protein-induced MSX1 and MSX2 inhibit myocardin-dependent smooth muscle gene transcription. Mol. Cell. Biol. 26, 9456–9470 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Liu, Y. et al. Kruppel-like factor 4 abrogates myocardin-induced activation of smooth muscle gene expression. J. Biol. Chem. 280, 9719–9727 (2005).

    CAS  PubMed  Google Scholar 

  96. Chen, F. et al. Hop is an unusual homeobox gene that modulates cardiac development. Cell 110, 713–723 (2002).

    CAS  PubMed  Google Scholar 

  97. Kook, H. et al. Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein HOP. J. Clin. Invest. 112, 863–871 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Shin, C. H. et al. Modulation of cardiac growth and development by HOP, an unusual homeodomain protein. Cell 110, 725–735 (2002).

    CAS  PubMed  Google Scholar 

  99. Cao, D. et al. Modulation of smooth muscle gene expression by association of histone acetyltransferases and deacetylases with myocardin. Mol. Cell. Biol. 25, 364–376 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Hanna, M. et al. Mechanical regulation of the proangiogenic factor CCN1/CYR61 gene requires the combined activities of MRTF-A and CREB-binding protein histone acetyltransferase. J. Biol. Chem. 284, 23125–23136 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Qiu, P. et al. Myocardin enhances Smad3-mediated transforming growth factor-β1 signaling in a CArG box-independent manner: Smad-binding element is an important cis element for SM22α transcription in vivo. Circ. Res. 97, 983–991 (2005).

    CAS  PubMed  Google Scholar 

  102. Oh, J. et al. Target gene-specific modulation of myocardin activity by GATA transcription factors. Mol. Cell. Biol. 24, 8519–8528 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Cooper, S. J., Trinklein, N. D., Nguyen, L. & Myers, R. M. Serum response factor binding sites differ in three human cell types. Genome Res. 17, 136–144 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Chen, J., Kitchen, C. M., Streb, J. W. & Miano, J. M. Myocardin: a component of a molecular switch for smooth muscle differentiation. J. Mol. Cell. Cardiol. 34, 1345–1356 (2002).

    CAS  PubMed  Google Scholar 

  105. Du, K. L. et al. Myocardin is a critical serum response factor cofactor in the transcriptional program regulating smooth muscle cell differentiation. Mol. Cell. Biol. 23, 2425–2437 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Yoshida, T. et al. Myocardin is a key regulator of CArG-dependent transcription of multiple smooth muscle marker genes. Circ. Res. 92, 856–864 (2003).

    CAS  PubMed  Google Scholar 

  107. Du, K. L. et al. Megakaryoblastic leukemia factor-1 transduces cytoskeletal signals and induces smooth muscle cell differentiation from undifferentiated embryonic stem cells. J. Biol. Chem. 279, 17578–17586 (2004).

    CAS  PubMed  Google Scholar 

  108. Li, S. et al. Requirement for serum response factor for skeletal muscle growth and maturation revealed by tissue-specific gene deletion in mice. Proc. Natl Acad. Sci. USA 102, 1082–1087 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Medjkane, S., Perez-Sanchez, C., Gaggioli, C., Sahai, E. & Treisman, R. Myocardin-related transcription factors and SRF are required for cytoskeletal dynamics and experimental metastasis. Nature Cell Biol. 11, 257–268 (2009).

    CAS  PubMed  Google Scholar 

  110. Verdoni, A. M., Aoyama, N., Ikeda, A. & Ikeda, S. Effect of destrin mutations on the gene expression profile in vivo. Physiol. Genomics 34, 9–21 (2008).

    CAS  PubMed  Google Scholar 

  111. Niu, Z., Li, A., Zhang, S. X. & Schwartz, R. J. Serum response factor micromanaging cardiogenesis. Curr. Opin. Cell Biol. 19, 618–627 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhao, Y., Samal, E. & Srivastava, D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436, 214–220 (2005). This paper shows for the first time that SRF regulates the expression of miRNAs. The identified miRNA, miR-1, controls cardiomyocyte proliferation.

    CAS  PubMed  Google Scholar 

  113. Liu, N. et al. MicroRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev. 22, 3242–3254 (2008). This paper shows that the miRNA miR-133a is required for cardiac development and negatively regulates SRF. See also reference 116.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Ivey, K. N. et al. MicroRNA regulation of cell lineages in mouse and human embryonic stem cells. Cell Stem Cell 2, 2192–29 (2008).

    Google Scholar 

  115. Xin, M. et al. MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. Genes Dev. 23, 2166–2178 (2009). This paper shows that SRF, together with members of the myocardin family, directly activates a bicistronic cluster of miRNAs, encoding miR-143 and miR-145, which in turn control smooth muscle phenotype switching through the regulation of numerous regulators of actin dynamics. See also references 117 and 118.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Niu, Z. et al. Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart. Proc. Natl Acad. Sci. USA 105, 17824–17829 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Cordes, K. R. et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature 460, 705–710 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Boettger, T. et al. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. J. Clin. Invest. 119, 2634–2647 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Small, E. M. et al. Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486. Proc. Natl Acad. Sci. USA. 107, 4218–4223 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Torrado, M. et al. Myocardin mRNA is augmented in the failing myocardium: expression profiling in the porcine model and human dilated cardiomyopathy. J. Mol. Med. 81, 566–577 (2003).

    CAS  PubMed  Google Scholar 

  121. Xing, W. et al. Myocardin induces cardiomyocyte hypertrophy. Circ. Res. 98, 1089–1097 (2006).

    CAS  PubMed  Google Scholar 

  122. Chang, J. et al. Inhibitory cardiac transcription factor, SRF-N, is generated by caspase 3 cleavage in human heart failure and attenuated by ventricular unloading. Circulation 108, 407–413 (2003).

    CAS  PubMed  Google Scholar 

  123. Chow, N. et al. Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype. Proc. Natl Acad. Sci. USA 104, 823–828 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Bell, R. D. et al. SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells. Nature Cell Biol. 11, 143–153 (2009).

    CAS  PubMed  Google Scholar 

  125. Owens, G. K., Kumar, M. S. & Wamhoff, B. R. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol. Rev. 84, 767–801 (2004).

    CAS  PubMed  Google Scholar 

  126. Carroll, A. et al. The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a pediatric oncology group study. Blood 78, 748–752 (1991).

    CAS  PubMed  Google Scholar 

  127. Ma, Z. et al. Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nature Genet. 28, 220–221 (2001).

    CAS  PubMed  Google Scholar 

  128. Mercher, T. et al. Recurrence of OTT-MAL fusion in t(1;22) of infant AML-M7. Genes Chromosomes Cancer 33, 22–28 (2002).

    CAS  PubMed  Google Scholar 

  129. Cen, B. et al. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes. Mol. Cell. Biol. 23, 6597–6608 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Descot, A. et al. OTT-MAL is a deregulated activator of serum response factor-dependent gene expression. Mol. Cell. Biol. 28, 6171–6181 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Sawada, T. et al. Fusion of OTT to BSAC results in aberrant up-regulation of transcriptional activity. J. Biol. Chem. 283, 26820–26828 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Mercher, T. et al. The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model. J. Clin. Invest. 119, 852–864 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Milyavsky, M. et al. Inactivation of myocardin and p16 during malignant transformation contributes to a differentiation defect. Cancer Cell 11, 133–146 (2007).

    CAS  PubMed  Google Scholar 

  134. Perot, G. et al. Strong smooth muscle differentiation is dependent on myocardin gene amplification in most human retroperitoneal leiomyosarcomas. Cancer Res. 69, 2269–2278 (2009).

    CAS  PubMed  Google Scholar 

  135. Heemers, H. V., Regan, K. M., Dehm, S. M. & Tindall, D. J. Androgen induction of the androgen receptor coactivator four and a half LIM domain protein-2: evidence for a role for serum response factor in prostate cancer. Cancer Res. 67, 10592–10599 (2007).

    CAS  PubMed  Google Scholar 

  136. Brandt, D. T. et al. SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of β1-integrin. Nature Cell Biol. 11, 557–568 (2009). This paper uncovers a role for MRTF in the control of cancer cell metastasis as a consequence of its regulation by SCAI, a transcriptional repressor that competes with MRTF for interaction with SRF. See also reference 109.

    CAS  PubMed  Google Scholar 

  137. Parlakian, A. et al. Targeted inactivation of serum response factor in the developing heart results in myocardial defects and embryonic lethality. Mol. Cell. Biol. 24, 5281–5289 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Miano, J. M. et al. Restricted inactivation of serum response factor to the cardiovascular system. Proc. Natl Acad. Sci. USA 101, 17132–17137 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Alberti, S. et al. Neuronal migration in the murine rostral migratory stream requires serum response factor. Proc. Natl Acad. Sci. USA 102, 6148–6153 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Ramanan, N. et al. SRF mediates activity-induced gene expression and synaptic plasticity but not neuronal viability. Nature Neurosci. 8, 759–767 (2005).

    CAS  PubMed  Google Scholar 

  141. Bhavsar, A. P., Guttman, J. A. & Finlay, B. B. Manipulation of host-cell pathways by bacterial pathogens. Nature 449, 827–834 (2007).

    CAS  PubMed  Google Scholar 

  142. Chhabra, E. S. & Higgs, H. N. The many faces of actin: matching assembly factors with cellular structures. Nature Cell Biol. 9, 1110–1121 (2007).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to all colleagues whose work could not be cited in full owing to space restrictions. We thank G. Posern and B. Knöll for comments on the manuscript. E.N.O. was supported by grants from the National Institutes of Health, the American Heart Association, the Robert A. Welch Foundation and the Leducq Foundation. A.N. acknowledges financial support by the DFG (No120/12-3 and SFB 773/A3).

Author information

Authors and Affiliations

  1. Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, 75390-9148, Texas, USA

    Eric N. Olson

  2. Abteilung Molekularbiologie, Eberhard-Karls-Universität Tübingen, Interfakultäres Institut für Zellbiologie, Auf der Morgenstelle 15, 72076, Tübingen, Germany

    Alfred Nordheim

Authors
  1. Eric N. Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alfred Nordheim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alfred Nordheim.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Eric N. Olson's homepage

Alfred Nordheim's homepage

Glossary

F-actin

A flexible, helical polymer of G-actin monomers that is 5–9 nm in diameter. An F-actin polymer is polar, displaying a plus (+) and a minus (−) end.

Focal adhesion

A cellular structure that links the ECM on the outside of the cell to the actin cytoskeleton inside the cell through integrin receptors.

Guanine nucleotide exchange factor

A protein that activates a specific small GTPase by catalysing the exchange of bound GDP for GTP.

Heterotrimeric G protein

One of a family of heterotrimeric cytoplasmic signal mediators composed of an -subunit containing a GTP-binding site and intrinsic GTPase activity, together with a hydrophobic and an often acylated β- and γ-protein subcomplex. The β- and γ-protein subcomplex may be activated by the dissociation of α–GTP, which is initiated by GTP exchange on the α-subunit.

Epithelial–mesenchymal transition

The transformation of an epithelial cell into a mesenchymal cell with migratory and invasive properties.

Adherens junction

A cell–cell adhesion complex that contains classical cadherins and catenins that are attached to cytoplasmic actin filaments.

SAP domain

(SAFA or SAFB, acinus and PIAS domain). A peptide motif found in several proteins known to contact DNA.

Leu zipper

A Leu-rich domain in a protein that binds to other proteins with a similar domain.

LIM domain

(Lin11, Isl1 and Mec3 domain). A zinc-binding protein domain that ligates two zinc ions. LIM domains mediate interactions with other proteins and have diverse functions as regulators of gene expression, cell adhesion and motility, and signal transduction.

RPEL domain

A protein domain containing the amino acid sequence Arg-Pro-X-X-X-Glu-Leu that is found triplicated in the myocardin family of transcriptional coactivators. RPEL domains form stable complexes with G-actin.

Barbed end

The plus (+) end of the polar F-actin polymer that, in contrast to the minus (−) end, is more active with regard to incorporation of G-actin into the polymer (polymer elongation).

Leiomyosarcoma

A rare type of cancer (a soft tissue sarcoma) that is a malignant neoplasm of smooth muscle origin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Olson, E., Nordheim, A. Linking actin dynamics and gene transcription to drive cellular motile functions. Nat Rev Mol Cell Biol 11, 353–365 (2010). https://doi.org/10.1038/nrm2890

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2890

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing