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.

  • Opinion
  • Published:

Introducing STRaNDs: shuttling transcriptional regulators that are non-DNA binding

Nature Reviews Molecular Cell Biology volume 17, pages 523–532 (2016)Cite this article

Subjects

Abstract

Many proteins originally identified as cytoplasmic — including many associated with the cytoskeleton or cell junctions — are increasingly being found in the nucleus, where they have specific functions. Here, we focus on proteins that translocate from the cytoplasm to the nucleus in response to external signals and regulate transcription without binding to DNA directly (for example, through interaction with transcription factors). We propose that proteins with such characteristics are classified as a distinct group of extracellular signalling effectors, and we suggest the term STRaND (shuttling transcriptional regulators and non-DNA binding) to refer to this group. Crucial roles of STRaNDs include linking cell morphology and adhesion with changes in transcriptional programmes in response to signals such as mechanical stresses.

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: Types of signalling pathway.
Figure 2: External signals sensed by STRaNDs and modes of their nuclear import.
Figure 3: Examples of regulation of STRaND nuclear entry by phosphorylation.

Similar content being viewed by others

References

  1. McCrea, P. D., Turck, C. W. & Gumbiner, B. A homolog of the armadillo protein in Drosophila (plakoglobin) associated with E-cadherin. Science 254, 1359–1361 (1991).

    Article  CAS  PubMed  Google Scholar 

  2. Riggleman, B., Schedl, P. & Wieschaus, E. Spatial expression of the Drosophila segment polarity gene armadillo is posttranscriptionally regulated by wingless. Cell 63, 549–560 (1990).

    Article  CAS  PubMed  Google Scholar 

  3. Peifer, M., Rauskolb, C., Williams, M., Riggleman, B. & Wieschaus, E. The segment polarity gene armadillo interacts with the wingless signaling pathway in both embryonic and adult pattern formation. Development 111, 1029–1043 (1991).

    CAS  PubMed  Google Scholar 

  4. Behrens, J. et al. Functional interaction of β-catenin with the transcription factor LEF-1. Nature 382, 638–642 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Molenaar, M. et al. XTcf-3 transcription factor mediates β-catenin-induced axis formation in Xenopus embryos. Cell 86, 391–399 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Huber, O. et al. Nuclear localization of β-catenin by interaction with transcription factor LEF-1. Mech. Dev. 59, 3–10 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Treisman, R. Identification and purification of a polypeptide that binds to the c-fos serum response element. EMBO J. 6, 2711–2717 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang, D. et al. Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell 105, 851–862 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. McGee, K. M., Vartiainen, M. K., Khaw, P. T., Treisman, R. & Bailly, M. Nuclear transport of the serum response factor coactivator MRTF-A is downregulated at tensional homeostasis. EMBO Rep. 12, 963–970 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. Yu-Wai-Man, C., Treisman, R., Bailly, M. & Khaw, P. T. The role of the MRTF-A/SRF pathway in ocular fibrosis. Invest. Ophthalmol. Vis. Sci. 55, 4560–4567 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Mouilleron, S., Langer, C. A., Guettler, S., McDonald, N. Q. & Treisman, R. Structure of a pentavalent G-actinċMRTF-A complex reveals how G-actin controls nucleocytoplasmic shuttling of a transcriptional coactivator. Sci. Signal. 4, ra40 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Esnault, C. et al. Rho-actin signaling to the MRTF coactivators dominates the immediate transcriptional response to serum in fibroblasts. Genes Dev. 28, 943–958 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

  17. Babakov, V. N. et al. RelA/NF-κB transcription factor associates with α-actinin-4. Exp. Cell Res. 314, 1030–1038 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Zhao, X., Hsu, K. S., Lim, J. H., Bruggeman, L. A. & Kao, H. Y. α-actinin 4 potentiates nuclear factor κ-light-chain-enhancer of activated B-cell (NF-κB) activity in podocytes independent of its cytoplasmic actin binding function. J. Biol. Chem. 290, 338–349 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Gringhuis, S. I., Kaptein, T. M., Wevers, B. A., Mesman, A. W. & Geijtenbeek, T. B. Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKKε- and CYLD-dependent Bcl3 activation. Nat. Commun. 5, 3898 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Massoumi, R., Chmielarska, K., Hennecke, K., Pfeifer, A. & Fassler, R. Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-κB signaling. Cell 125, 665–677 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Mellad, J. A., Warren, D. T. & Shanahan, C. M. Nesprins LINC the nucleus and cytoskeleton. Curr. Opin. Cell Biol. 23, 47–54 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Schaller, M. D. Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. J. Cell Sci. 123, 1007–1013 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Mitra, S. K., Hanson, D. A. & Schlaepfer, D. D. Focal adhesion kinase: in command and control of cell motility. Nat. Rev. Mol. Cell Biol. 6, 56–68 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Lim, S. T. et al. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol. Cell 29, 9–22 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Luo, S. W. et al. Regulation of heterochromatin remodelling and myogenin expression during muscle differentiation by FAK interaction with MBD2. EMBO J. 28, 2568–2582 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lim, S. T. et al. Nuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression. J. Cell Biol. 197, 907–919 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Golubovskaya, V. M., Finch, R. & Cance, W. G. Direct interaction of the N-terminal domain of focal adhesion kinase with the N-terminal transactivation domain of p53. J. Biol. Chem. 280, 25008–25021 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Serrels, A. et al. Nuclear FAK controls chemokine transcription, tregs, and evasion of anti-tumor immunity. Cell 163, 160–173 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Premaraj, S., Souza, I. & Premaraj, T. Mechanical loading activates β-catenin signaling in periodontal ligament cells. Angle Orthod. 81, 592–599 (2011).

    Article  PubMed  Google Scholar 

  30. Chen, J. H., Chen, W. L., Sider, K. L., Yip, C. Y. & Simmons, C. A. β-catenin mediates mechanically regulated, transforming growth factor-β1-induced myofibroblast differentiation of aortic valve interstitial cells. Arterioscler. Thromb. Vasc. Biol. 31, 590–597 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Du, J. et al. Extracellular matrix stiffness dictates Wnt expression through integrin pathway. Sci. Rep. 6, 20395 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cavallaro, U. & Dejana, E. Adhesion molecule signalling: not always a sticky business. Nat. Rev. Mol. Cell Biol. 12, 189–197 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. McCrea, P. D. & Gottardi, C. J. Beyond β-catenin: prospects for a larger catenin network in the nucleus. Nat. Rev. Mol. Cell Biol. 17, 55–64 (2016).

    Article  CAS  PubMed  Google Scholar 

  34. Zhao, B., Tumaneng, K. & Guan, K. L. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat. Cell Biol. 13, 877–883 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chan, S. W. et al. Hippo pathway-independent restriction of TAZ and YAP by angiomotin. J. Biol. Chem. 286, 7018–7026 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhao, B. et al. Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev. 25, 51–63 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  39. Zhao, B. et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21, 2747–2761 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Aragona, M. et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154, 1047–1059 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Azzolin, L. et al. YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell 158, 157–170 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Matsui, Y. & Lai, Z. C. Mutual regulation between Hippo signaling and actin cytoskeleton. Protein Cell 4, 904–910 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Strano, S. et al. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA damage. Mol. Cell 18, 447–459 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Basu, S., Totty, N. F., Irwin, M. S., Sudol, M. & Downward, J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol. Cell 11, 11–23 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Lapi, E. et al. PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. Mol. Cell 32, 803–814 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Levy, D., Reuven, N. & Shaul, Y. A regulatory circuit controlling Itch-mediated p73 degradation by Runx. J. Biol. Chem. 283, 27462–27468 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Vitolo, M. I. et al. The RUNX2 transcription factor cooperates with the YES-associated protein, YAP65, to promote cell transformation. Cancer Biol. Ther. 6, 856–863 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Miller, M. K. et al. The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules. J. Mol. Biol. 333, 951–964 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Kojic, S. et al. A novel role for cardiac ankyrin repeat protein Ankrd1/CARP as a co-activator of the p53 tumor suppressor protein. Arch. Biochem. Biophys. 502, 60–67 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. Zou, Y. et al. CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway. Development 124, 793–804 (1997).

    CAS  PubMed  Google Scholar 

  51. Kojic, S., Radojkovic, D. & Faulkner, G. Muscle ankyrin repeat proteins: their role in striated muscle function in health and disease. Crit. Rev. Clin. Lab. Sci. 48, 269–294 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Berry, F. B., O'Neill, M. A., Coca-Prados, M. & Walter, M. A. FOXC1 transcriptional regulatory activity is impaired by PBX1 in a filamin A-mediated manner. Mol. Cell. Biol. 25, 1415–1424 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. D'Addario, M., Arora, P. D., Ellen, R. P. & McCulloch, C. A. Interaction of p38 and Sp1 in a mechanical force-induced, β1 integrin-mediated transcriptional circuit that regulates the actin-binding protein filamin-A. J. Biol. Chem. 277, 47541–47550 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Sasaki, A., Masuda, Y., Ohta, Y., Ikeda, K. & Watanabe, K. Filamin associates with Smads and regulates transforming growth factor-β signaling. J. Biol. Chem. 276, 17871–17877 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Lange, A. et al. Classical nuclear localization signals: definition, function, and interaction with importin α. J. Biol. Chem. 282, 5101–5105 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Van Impe, K. et al. A new role for nuclear transport factor 2 and Ran: nuclear import of CapG. Traffic 9, 695–707 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Fagotto, F., Gluck, U. & Gumbiner, B. M. Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of β-catenin. Curr. Biol. 8, 181–190 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Lu, M. et al. A code for RanGDP binding in ankyrin repeats defines a nuclear import pathway. Cell 157, 1130–1145 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Zuchero, J. B., Belin, B. & Mullins, R. D. Actin binding to WH2 domains regulates nuclear import of the multifunctional actin regulator JMY. Mol. Biol. Cell 23, 853–863 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Pawlowski, R., Rajakyla, E. K., Vartiainen, M. K. & Treisman, R. An actin-regulated importin α/β-dependent extended bipartite NLS directs nuclear import of MRTF-A. EMBO J. 29, 3448–3458 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lu, M. et al. Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP. Cancer Cell 23, 618–633 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Herbst, A. et al. Comprehensive analysis of β-catenin target genes in colorectal carcinoma cell lines with deregulated Wnt/β-catenin signaling. BMC Genomics 15, 74 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Gordon, M. D. & Nusse, R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J. Biol. Chem. 281, 22429–22433 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Guruharsha, K. G., Kankel, M. W. & Artavanis-Tsakonas, S. The Notch signalling system: recent insights into the complexity of a conserved pathway. Nat. Rev. Genet. 13, 654–666 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ranganathan, P., Weaver, K. L. & Capobianco, A. J. Notch signalling in solid tumours: a little bit of everything but not all the time. Nat. Rev. Cancer 11, 338–351 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Vives, V. et al. ASPP2 is a haploinsufficient tumor suppressor that cooperates with p53 to suppress tumor growth. Genes Dev. 20, 1262–1267 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Slee, E. A. et al. The N-terminus of a novel isoform of human iASPP is required for its cytoplasmic localization. Oncogene 23, 9007–9016 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. 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).

    Article  CAS  PubMed  Google Scholar 

  69. Shikama, N. et al. A novel cofactor for p300 that regulates the p53 response. Mol. Cell 4, 365–376 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Aksenova, V. et al. Actin-binding protein alpha-actinin 4 (ACTN4) is a transcriptional co-activator of RelA/p65 sub-unit of NF-kB. Oncotarget 4, 362–372 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Kim, M., Kim, T., Johnson, R. L. & Lim, D. S. Transcriptional co-repressor function of the Hippo pathway transducers YAP and TAZ. Cell Rep. 11, 270–282 (2015).

    Article  CAS  PubMed  Google Scholar 

  72. Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. MacDonald, B. T., Tamai, K. & He, X. Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9–26 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Dong, Y. et al. RBPjκ-dependent Notch signaling regulates mesenchymal progenitor cell proliferation and differentiation during skeletal development. Development 137, 1461–1471 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Rangarajan, A. et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 20, 3427–3436 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yoshioka, S. et al. WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/β-catenin pathway. Mol. Cancer Res. 10, 469–482 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ochoa-Hernandez, A. B. et al. Peripheral T-lymphocytes express WNT7A and its restoration in leukemia-derived lymphoblasts inhibits cell proliferation. BMC Cancer 12, 60 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chien, A. J. et al. Activated Wnt/β-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model. Proc. Natl Acad. Sci. USA 106, 1193–1198 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Stratton, M. R., Campbell, P. J. & Futreal, P. A. The cancer genome. Nature 458, 719–724 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Khurana, S. et al. Familial focal segmental glomerulosclerosis (FSGS)-linked α-actinin 4 (ACTN4) protein mutants lose ability to activate transcription by nuclear hormone receptors. J. Biol. Chem. 287, 12027–12035 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tosello, V. & Ferrando, A. A. The NOTCH signaling pathway: role in the pathogenesis of T-cell acute lymphoblastic leukemia and implication for therapy. Ther. Adv. Hematol. 4, 199–210 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Stransky, N. et al. The mutational landscape of head and neck squamous cell carcinoma. Science 333, 1157–1160 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012).

  84. Weng, A. P. et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306, 269–271 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Lamande, S. R. et al. Mutations in TRPV4 cause an inherited arthropathy of hands and feet. Nat. Genet. 43, 1142–1146 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Rock, M. J. et al. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat. Genet. 40, 999–1003 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Landoure, G. et al. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat. Genet. 42, 170–174 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Nilius, B. & Owsianik, G. Channelopathies converge on TRPV4. Nat. Genet. 42, 98–100 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Zhao, Y. et al. Unusual localization and translocation of TRPV4 protein in cultured ventricular myocytes of the neonatal rat. Eur. J. Histochem. 56, e32 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Deng, H. X. et al. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat. Genet. 42, 165–169.

  91. Chung, M. K., Lee, H., Mizuno, A., Suzuki, M. & Caterina, M. J. TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J. Biol. Chem. 279, 21569–21575 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Cenac, N. et al. Potentiation of TRPV4 signalling by histamine and serotonin: an important mechanism for visceral hypersensitivity. Gut 59, 481–488 (2012).

    Article  CAS  Google Scholar 

  93. Muramatsu, S. et al. Functional gene screening system identified TRPV4 as a regulator of chondrogenic differentiation. J. Biol. Chem. 282, 32158–32167 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Barry, E. R. et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature 493, 106–110 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Azzolin, L. et al. Role of TAZ as mediator of Wnt signaling. Cell 151, 1443–1456 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Rosenbluh, J. et al. β-catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 151, 1457–1473 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Heallen, T. et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458–461 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Liu, C. Y. et al. PP1 cooperates with ASPP2 to dephosphorylate and activate TAZ. J. Biol. Chem. 286, 5558–5566 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Royer, C. et al. ASPP2 links the apical lateral polarity complex to the regulation of YAP activity in epithelial cells. PLoS ONE 9, e111384 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wang, Y. et al. ASPP2 controls epithelial plasticity and inhibits metastasis through β-catenin-dependent regulation of ZEB1. Nat. Cell Biol. 16, 1092–1104 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Taniguchi, K. et al. A gp130–Src–YAP module links inflammation to epithelial regeneration. Nature 519, 57–62 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Yimlamai, D. et al. Hippo pathway activity influences liver cell fate. Cell 157, 1324–1338 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kode, A. et al. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 506, 240–244 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Peignon, G. et al. Complex interplay between β-catenin signalling and Notch effectors in intestinal tumorigenesis. Gut 60, 166–176 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Charbonney, E., Speight, P., Masszi, A., Nakano, H. & Kapus, A. β-catenin and Smad3 regulate the activity and stability of myocardin-related transcription factor during epithelial–myofibroblast transition. Mol. Biol. Cell 22, 4472–4485 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Speight, P., Nakano, H., Kelley, T. J., Hinz, B. & Kapus, A. Differential topical susceptibility to TGFβ in intact and injured regions of the epithelium: key role in myofibroblast transition. Mol. Biol. Cell 24, 3326–3336 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Gomez, E. W., Chen, Q. K., Gjorevski, N. & Nelson, C. M. Tissue geometry patterns epithelial-mesenchymal transition via intercellular mechanotransduction. J. Cell. Biochem. 110, 44–51 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Lim, S. T. Nuclear FAK: a new mode of gene regulation from cellular adhesions. Mol. Cells 36, 1–6 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wei, X. et al. Kindlin-2 mediates activation of TGF-β/Smad signaling and renal fibrosis. J. Am. Soc. Nephrol. 24, 1387–1398 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Buti, L. et al. Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host. Proc. Natl Acad. Sci. USA 108, 9238–9243 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Samuels-Lev, Y. et al. ASPP proteins specifically stimulate the apoptotic function of p53. Mol. Cell 8, 781–794 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Bergamaschi, D. et al. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat. Genet. 33, 162–167 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Yamashita, M., Nitta, E. & Suda, T. Aspp1 preserves hematopoietic stem cell pool integrity and prevents malignant transformation. Cell Stem Cell 17, 23–34 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Orsulic, S., Huber, O., Aberle, H., Arnold, S. & Kemler, R. E-cadherin binding prevents beta-catenin nuclear localization and beta-catenin/LEF-1-mediated transactivation. J. Cell Sci. 112, 1237–1245 (1999).

    CAS  PubMed  Google Scholar 

  116. Anastas, J. N. & Moon, R. T. WNT signalling pathways as therapeutic targets in cancer. Nat. Rev. Cancer 13, 11–26 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. Khurana, S., Chakraborty, S., Cheng, X., Su, Y. T. & Kao, H. Y. The actin-binding protein, actinin alpha 4 (ACTN4), is a nuclear receptor coactivator that promotes proliferation of MCF-7 breast cancer cells. J. Biol. Chem. 286, 1850–1859 (2011).

    Article  CAS  PubMed  Google Scholar 

  118. An, H. T., Kim, J., Yoo, S. & Ko, J. Small leucine zipper protein (sLZIP) negatively regulates skeletal muscle differentiation via interaction with α-actinin-4. J. Biol. Chem. 289, 4969–4979 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. Archer, S. K., Claudianos, C. & Campbell, H. D. Evolution of the gelsolin family of actin-binding proteins as novel transcriptional coactivators. Bioessays 27, 388–396 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Gettemans, J. et al. Nuclear actin-binding proteins as modulators of gene transcription. Traffic 6, 847–857 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Markus, S. M. et al. Identification and characterization of ART-27, a novel coactivator for the androgen receptor N terminus. Mol. Biol. Cell 13, 670–682 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Sun, S. et al. UXT is a novel and essential cofactor in the NF-κB transcriptional enhanceosome. J. Cell Biol. 178, 231–244 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Ludwig Institute for Cancer Research. M.L. is supported by the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (No.TP2014029) and the Samuel Waxman Cancer Research Foundation Co-PI Program. The authors thank Colin Goding for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Nuffield Department of Medicine, Mary R. Muers and Xin Lu are at the Ludwig Institute for Cancer Research, University of Oxford, UK.,

    Mary R. Muers & Xin Lu

  2. China; he was previously at the Ludwig Institute for Cancer Researchuffield Department of Medicine, Min Lu is currently at the State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, University of Oxford, UK.,

    Min Lu

  3. he was previously at the Ludwig Institute for Cancer Researchuffield Department of Medicine, University of Oxford, UK., University of Oxford, UK.,

    Min Lu

Authors
  1. Min Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mary R. Muers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xin Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xin Lu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Related links

Related links

FURTHER INFORMATION

UniProt Human Reviewed Reference Proteins

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lu, M., Muers, M. & Lu, X. Introducing STRaNDs: shuttling transcriptional regulators that are non-DNA binding. Nat Rev Mol Cell Biol 17, 523–532 (2016). https://doi.org/10.1038/nrm.2016.41

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm.2016.41

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