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:

DEP domains: structurally similar but functionally different

Nature Reviews Molecular Cell Biology volume 15, pages 357–362 (2014)Cite this article

Subjects

Abstract

The Dishevelled, EGL-10 and pleckstrin (DEP) domain is a globular protein domain that is present in about ten human protein families with well-defined structural features. A picture is emerging that DEP domains mainly function in the spatial and temporal control of diverse signal transduction events by recruiting proteins to the plasma membrane. DEP domains can interact with various partners at the membrane, including phospholipids and membrane receptors, and their binding is subject to regulation.

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: Domain architecture of mammalian DEP domain-containing proteins.
Figure 2: DEP domain structures.
Figure 3: Diversity of pathways that are regulated by DEP domain-containing proteins.

Similar content being viewed by others

References

  1. Kholodenko, B. N., Hoek, J. B. & Westerhoff, H. V. Why cytoplasmic signalling proteins should be recruited to cell membranes. Trends Cell Biol. 10, 173–178 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Scott, J. D. & Pawson, T. Cell signaling in space and time: where proteins come together and when they're apart. Science 326, 1220–1224 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kharrat, A. et al. Conformational stability studies of the pleckstrin DEP domain: definition of the domain boundaries. Biochim. Biophys. Acta 1385, 157–164 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Civera, C., Simon, B., Stier, G., Sattler, M. & Macias, M. J. Structure and dynamics of the human pleckstrin DEP domain: distinct molecular features of a novel DEP domain subfamily. Proteins 58, 354–366 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Ponting, C. P. & Bork, P. Pleckstrin's repeat performance: a novel domain in G-protein signaling? Trends Biochem. Sci. 21, 245–246 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Sierra, D. A. et al. Evolution of the regulators of G-protein signaling multigene family in mouse and human. Genomics 79, 177–185 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Dillman, A. R., Minor, P. J. & Sternberg, P. W. Origin and evolution of dishevelled. G3 (Bethesda) 3, 251–262 (2013).

    Article  Google Scholar 

  8. Ross, E. M. & Wilkie, T. M. GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu. Rev. Biochem. 69, 795–827 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Schwarz-Romond, T., Metcalfe, C. & Bienz, M. Dynamic recruitment of axin by Dishevelled protein assemblies. J. Cell Sci. 120, 2402–2412 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Julius, M. A. et al. Domains of axin and disheveled required for interaction and function in wnt signaling. Biochem. Biophys. Res. Commun. 276, 1162–1169 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Pawson, T., Gish, G. D. & Nash, P. SH2 domains, interaction modules and cellular wiring. Trends Cell Biol. 11, 504–511 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Grebien, F. et al. Targeting the SH2-kinase interface in Bcr–Abl inhibits leukemogenesis. Cell 147, 306–319 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wong, H. C. et al. Structural basis of the recognition of the dishevelled DEP domain in the Wnt signaling pathway. Nature Struct. Biol. 7, 1178–1184 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Axelrod, J. D., Miller, J. R., Shulman, J. M., Moon, R. T. & Perrimon, N. Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways. Genes Dev. 12, 2610–2622 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Consonni, S. V., Gloerich, M., Spanjaard, E. & Bos, J. L. cAMP regulates DEP domain-mediated binding of the guanine nucleotide exchange factor Epac1 to phosphatidic acid at the plasma membrane. Proc. Natl Acad. Sci. USA 109, 3814–3819 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Simons, M. et al. Electrochemical cues regulate assembly of the Frizzled/Dishevelled complex at the plasma membrane during planar epithelial polarization. Nature Cell Biol. 11, 286–294 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Cheever, M. L. et al. Crystal structure of the multifunctional Gβ5–RGS9 complex. Nature Struct. Mol. Biol. 15, 155–162 (2008).

    Article  CAS  Google Scholar 

  18. Masuho, I., Wakasugi-Masuho, H., Posokhova, E. N., Patton, J. R. & Martemyanov, K. A. Type 5 G protein beta subunit (Gbeta5) controls the interaction of regulator of G protein signaling 9 (RGS9) with membrane anchors. J. Biol. Chem. 286, 21806–21813 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yu, A. et al. Association of Dishevelled with the clathrin AP-2 adaptor is required for Frizzled endocytosis and planar cell polarity signaling. Dev. Cell 12, 129–141 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tauriello, D. V. et al. Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled. Proc. Natl Acad. Sci. USA 109, E812–E820 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Perrimon, N. & Mahowald, A. P. Multiple functions of segment polarity genes in Drosophila. Dev. Biol. 119, 587–600 (1987).

    Article  CAS  PubMed  Google Scholar 

  22. Pan, W. J. et al. Characterization of function of three domains in dishevelled-1: DEP domain is responsible for membrane translocation of dishevelled-1. Cell Res. 14, 324–330 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Schwarz-Romond, T. et al. The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization. Nature Struct. Mol. Biol. 14, 484–492 (2007).

    Article  CAS  Google Scholar 

  24. Wong, H. C. et al. Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. Mol. Cell 12, 1251–1260 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Clevers, H. & Nusse, R. Wnt/β-catenin signaling and disease. Cell 149, 1192–1205 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Gao, B. Wnt regulation of planar cell polarity (PCP). Curr. Top. Dev. Biol. 101, 263–295 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Schulte, G. & Bryja, V. The Frizzled family of unconventional G-protein-coupled receptors. Trends Pharmacol. Sci. 28, 518–525 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Huang, X. et al. Phosphorylation of Dishevelled by protein kinase RIPK4 regulates Wnt signaling. Science 339, 1441–1445 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yanfeng, W. A., Tan, C., Fagan, R. J. & Klein, P. S. Phosphorylation of frizzled-3. J. Biol. Chem. 281, 11603–11609 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Mlodzik, M. Planar cell polarization: do the same mechanisms regulate Drosophila tissue polarity and vertebrate gastrulation? Trends Genet. 18, 564–571 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Chasse, S. A. & Dohlman, H. G. RGS proteins: G protein-coupled receptors meet their match. Assay Drug Dev. Technol. 1, 357–364 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Narayanan, V. et al. Intramolecular interaction between the DEP domain of RGS7 and the Gβ5 subunit. Biochemistry 46, 6859–6870 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Martemyanov, K. A. et al. The DEP domain determines subcellular targeting of the GTPase activating protein RGS9 in vivo. J. Neurosci. 23, 10175–10181 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Anderson, G. R., Posokhova, E. & Martemyanov, K. A. The R7 RGS protein family: multi-subunit regulators of neuronal G protein signaling. Cell Biochem. Biophys. 54, 33–46 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ballon, D. R. et al. DEP-domain-mediated regulation of GPCR signaling responses. Cell 126, 1079–1093 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Sandiford, S. L. & Slepak, V. Z. The Gβ5-RGS7 complex selectively inhibits muscarinic M3 receptor signaling via the interaction between the third intracellular loop of the receptor and the DEP domain of RGS7. Biochemistry 48, 2282–2289 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. de Rooij, J. et al. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 396, 474–477 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Gloerich, M. et al. Spatial regulation of cyclic AMP-Epac1 signaling in cell adhesion by ERM proteins. Mol. Cell. Biol. 30, 5421–5431 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gloerich, M. & Bos, J. L. Epac: defining a new mechanism for cAMP action. Annu. Rev. Pharmacol. Toxicol. 50, 355–375 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Rehmann, H., Das, J., Knipscheer, P., Wittinghofer, A. & Bos, J. L. Structure of the cyclic-AMP-responsive exchange factor Epac2 in its auto-inhibited state. Nature 439, 625–628 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Ponsioen, B. et al. Direct spatial control of Epac1 by cyclic AMP. Mol. Cell. Biol. 29, 2521–2531 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li, S. et al. Mechanism of intracellular cAMP sensor Epac2 activation: cAMP-induced conformational changes identified by amide hydrogen/deuterium exchange mass spectrometry (DXMS). J. Biol. Chem. 286, 17889–17897 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li, Y. et al. The RAP1 guanine nucleotide exchange factor Epac2 couples cyclic AMP and Ras signals at the plasma membrane. J. Biol. Chem. 281, 2506–2514 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Hill, K. et al. Regulation of P-Rex1 by phosphatidylinositol (3,4,5)-trisphosphate and Gβγ subunits. J. Biol. Chem. 280, 4166–4173 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Pandiella, A. & Montero, J. C. Molecular pathways: p-rex in cancer. Clin. Cancer Res. 19, 4564–4569 (2013).

    Article  CAS  PubMed  Google Scholar 

  46. Sosa, M. S. et al. Identification of the Rac-GEF P-Rex1 as an essential mediator of ErbB signaling in breast cancer. Mol. Cell 40, 877–892 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Qin, J. et al. Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis. Oncogene 28, 1853–1863 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Urano, D., Nakata, A., Mizuno, N., Tago, K. & Itoh, H. Domain-domain interaction of P-Rex1 is essential for the activation and inhibition by G protein betagamma subunits and PKA. Cell Signal 20, 1545–1554 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Ma, A. D., Brass, L. F. & Abrams, C. S. Pleckstrin associates with plasma membranes and induces the formation of membrane projections: requirements for phosphorylation and the NH2-terminal PH domain. J. Cell Biol. 136, 1071–1079 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Stenmark, H. & Aasland, R. FYVE-finger proteins--effectors of an inositol lipid. J. Cell Sci. 112, 4175–4183 (1999).

    CAS  PubMed  Google Scholar 

  51. Vassilatis, D. K. et al. The G protein-coupled receptor repertoires of human and mouse. Proc. Natl Acad. Sci. USA 100, 4903–4908 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Peterson, T. R. et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137, 873–886 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank H. Rehmann, University Medical Center Utrecht, The Netherlands, for providing the ribbon diagrams of DVL, EPAC, RGS9 and pleckstrin DEP.

Author information

Authors and Affiliations

  1. Molecular Cancer Research and Cancer Genomics Netherlands, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, Utrecht, 3584 CG, Utrecht, The Netherlands

    Sarah V. Consonni

  2. Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands

    Madelon M. Maurice

  3. Molecular Cancer Research and Cancer Genomics Netherlands, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, Utrecht, 3584 CG, Utrecht, The Netherlands

    Johannes L. Bos

Authors
  1. Sarah V. Consonni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Madelon M. Maurice
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johannes L. Bos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Johannes L. Bos.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

FURTHER INFORMATION

SMART database

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Consonni, S., Maurice, M. & Bos, J. DEP domains: structurally similar but functionally different. Nat Rev Mol Cell Biol 15, 357–362 (2014). https://doi.org/10.1038/nrm3791

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3791

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