Skip to main content
SpringerLink
Log in

Role of DLC-1, a tumor suppressor protein with RhoGAP activity, in regulation of the cytoskeleton and cell motility

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

DLC-1 was originally identified as a potential tumor suppressor. One of the key biochemical functions of DLC-1 is to serve as a GTPase activating protein (GAP) for members of the Rho family of GTPases, particularly Rho A-C and Cdc 42. Since these GTPases are critically involved in regulation of the cytoskeleton and cell migration, it seems clear that DLC-1 will also influence these processes. In this review we examine basic aspects of the actin cyoskeleton and how it relates to cell motility. We then delineate the characteristics of DLC-1 and other members of its family, and describe how they may have multiple effects on the regulation of cell polarity, actin organization, and cell migration.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Yang, J., & Weinberg, R. A. (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Developmental Cell, 14(6), 818–829.

    Article  PubMed  CAS  Google Scholar 

  2. Simpson, K. J., Selfors, L. M., Bui, J., Reynolds, A., Leake, D., Khvorova, A., et al. (2008). Identification of genes that regulate epithelial cell migration using an siRNA screening approach. Nature Cell Biology, [epub ahead of print] http://www.nature.com/ncb/journal/v10/n19/abs/ncb1762.html.

  3. Vicente-Manzanares, M., Webb, D. J., & Horwitz, A. R. (2005). Cell migration at a glance. Journal of Cell Science, 118(Pt 21), 4917–4919.

    Article  PubMed  CAS  Google Scholar 

  4. Ridley, A. J., Schwartz, M. A., Burridge, K., Firtel, R. A., Ginsberg, M. H., Borisy, G., et al. (2003). Cell migration: integrating signals from front to back. Science, 302(5651), 1704–1709.

    Article  PubMed  CAS  Google Scholar 

  5. Berrier, A. L., & Yamada, K. M. (2007). Cell-matrix adhesion. Journal of Cellular Physiology, 213(3), 565–573.

    Article  PubMed  CAS  Google Scholar 

  6. Etienne-Manneville, S., & Hall, A. (2002). Rho GTPases in cell biology. Nature, 420(6916), 629–635.

    Article  PubMed  CAS  Google Scholar 

  7. Jaffe, A. B., & Hall, A. (2005). Rho GTPases: biochemistry and biology. Annual Review of Cell and Developmental Biology, 21, 247–269.

    Article  PubMed  CAS  Google Scholar 

  8. Durkin, M. E., Yuan, B. Z., Zhou, X., Zimonjic, D. B., Lowy, D. R., Thorgeirsson, S. S., et al. (2007). DLC-1:a Rho GTPase-activating protein and tumour suppressor. Journal of Cellular and Molecular Medicine, 11(5), 1185–1207.

    Article  PubMed  CAS  Google Scholar 

  9. Hynes, R. O. (2002). Integrins: bidirectional, allosteric signaling machines. Cell, 110(6), 673–687.

    Article  PubMed  CAS  Google Scholar 

  10. Larsen, M., Artym, V. V., Green, J. A., & Yamada, K. M. (2006). The matrix reorganized: extracellular matrix remodeling and integrin signaling. Current Opinion in Cell Biology, 18(5), 463–471.

    Article  PubMed  CAS  Google Scholar 

  11. Zaidel-Bar, R., Cohen, M., Addadi, L., & Geiger, B. (2004). Hierarchical assembly of cell-matrix adhesion complexes. Biochemical Society Transactions, 32(Pt3), 416–420.

    Article  PubMed  CAS  Google Scholar 

  12. Del Pozo, M. A., & Schwartz, M. A. (2007). Rac, membrane heterogeneity, caveolin and regulation of growth by integrins. Trends in Cell Biology, 17(5), 246–250.

    Article  PubMed  CAS  Google Scholar 

  13. Juliano, R. L., Reddig, P., Alahari, S., Edin, M., Howe, A., & Aplin, A. (2004). Integrin regulation of cell signalling and motility. Biochemical Society Transactions, 32(Pt3), 443–446.

    Article  PubMed  CAS  Google Scholar 

  14. Moissoglu, K., & Schwartz, M. A. (2006). Integrin signalling in directed cell migration. Biology of the Cell, 98(9), 547–555.

    Article  PubMed  CAS  Google Scholar 

  15. Ridley, A. J., & Hall, A. (2004). Snails, Swiss, and serum: the solution for Rac ‘n’ Rho. Cell, 116(2 Suppl), S23–25, 22 p following S25.

    Article  PubMed  CAS  Google Scholar 

  16. Wennerberg, K., & Der, C. J. (2004). Rho-family GTPases: it’s not only Rac and Rho (and I like it). Journal of Cell Science, 117(Pt 8), 1301–1312.

    Article  PubMed  CAS  Google Scholar 

  17. Burridge, K., & Wennerberg, K. (2004). Rho and Rac take center stage. Cell, 116(2), 167–179.

    Article  PubMed  CAS  Google Scholar 

  18. Nalbant, P., Hodgson, L., Kraynov, V., Toutchkine, A., & Hahn, K. M. (2004). Activation of endogenous Cdc42 visualized in living cells. Science, 305(5690), 1615–1619.

    Article  PubMed  CAS  Google Scholar 

  19. Pertz, O., Hodgson, L., Klemke, R. L., & Hahn, K. M. (2006). Spatiotemporal dynamics of RhoA activity in migrating cells. Nature, 440(7087), 1069–1072.

    Article  PubMed  CAS  Google Scholar 

  20. Weaver, A. M., Young, M. E., Lee, W. L., & Cooper, J. A. (2003). Integration of signals to the Arp2/3 complex. Current Opinion in Cell Biology, 15(1), 23–30.

    Article  PubMed  CAS  Google Scholar 

  21. Bensenor, L. B., Kan, H. M., Wang, N., Wallrabe, H., Davidson, L. A., Cai, Y., et al. (2007). IQGAP1 regulates cell motility by linking growth factor signaling to actin assembly. Journal of Cell Science, 120(Pt 4), 658–669.

    Article  PubMed  CAS  Google Scholar 

  22. Huang, T. Y., DerMardirossian, C., & Bokoch, G. M. (2006). Cofilin phosphatases and regulation of actin dynamics. Current Opinion in Cell Biology, 18(1), 26–31.

    Article  PubMed  CAS  Google Scholar 

  23. Yamaguchi, H., & Condeelis, J. (2007). Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochimica et Biophysica Acta, 1773(5), 642–652.

    PubMed  CAS  Google Scholar 

  24. Kumar, R., Gururaj, A. E., & Barnes, C. J. (2006). p21-activated kinases in cancer. Nature Reviews Cancer, 6(6), 459–471.

    Article  PubMed  CAS  Google Scholar 

  25. Cai, L., Marshall, T. W., Uetrecht, A. C., Schafer, D. A., & Bear, J. E. (2007). Coronin 1B coordinates Arp2/3 complex and cofilin activities at the leading edge. Cell, 128(5), 915–929.

    Article  PubMed  CAS  Google Scholar 

  26. Krause, M., Dent, E. W., Bear, J. E., Loureiro, J. J., & Gertler, F. B. (2003). Ena/VASP proteins: regulators of the actin cytoskeleton and cell migration. Annual Review of Cell and Developmental Biology, 19, 541–564.

    Article  PubMed  CAS  Google Scholar 

  27. Fukata, Y., Amano, M., & Kaibuchi, K. (2001). Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends in Pharmacological Sciences, 22(1), 32–39.

    Article  PubMed  CAS  Google Scholar 

  28. Pellegrin, S., & Mellor, H. (2007). Actin stress fibres. Journal of Cell Science, 120(Pt 20), 3491–3499.

    Article  PubMed  CAS  Google Scholar 

  29. Watanabe, N., & Higashida, C. (2004). Formins: processive cappers of growing actin filaments. Experimental Cell Research, 301(1), 16–22.

    Article  PubMed  CAS  Google Scholar 

  30. Nayal, A., Webb, D. J., Brown, C. M., Schaefer, E. M., Vicente-Manzanares, M., & Horwitz, A. R. (2006). Paxillin phosphorylation at Ser273 localizes a GIT1-PIX-PAK complex and regulates adhesion and protrusion dynamics. Journal of Cell Biology, 173(4), 587–589.

    Article  PubMed  CAS  Google Scholar 

  31. Nishiya, N., Kiosses, W. B., Han, J., & Ginsberg, M. H. (2005). An alpha4 integrin-paxillin-Arf-GAP complex restricts Rac activation to the leading edge of migrating cells. Nature Cell Biology, 7(4), 343–352.

    Article  PubMed  CAS  Google Scholar 

  32. Dow, L. E., & Humbert, P. O. (2007). Polarity regulators and the control of epithelial architecture, cell migration, and tumorigenesis. International Review of Cytology, 262, 253–302.

    Article  PubMed  CAS  Google Scholar 

  33. Myers, K. R., & Casanova, J. E. (2008). Regulation of actin cytoskeleton dynamics by Arf-family GTPases. Trends in Cell Biology, 18(4), 184–192.

    Article  PubMed  CAS  Google Scholar 

  34. Balasubramanian, N., Scott, D. W., Castle, J. D., Casanova, J. E., & Schwartz, M. A. (2007). Arf6 and microtubules in adhesion-dependent trafficking of lipid rafts. Nature Cell Biology, 9(12), 1381–1391.

    Article  PubMed  CAS  Google Scholar 

  35. Palamidessi, A., Frittoli, E., Garre, M., Faretta, M., Mione, M., Testa, I., et al. (2008). Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration. Cell, 134(1), 135–147.

    Article  PubMed  CAS  Google Scholar 

  36. Bos, J. L., Rehmann, H., & Wittinghofer, A. (2007). GEFs and GAPs: critical elements in the control of small G proteins. Cell, 129(5), 865–877.

    Article  PubMed  CAS  Google Scholar 

  37. Rossman, K. L., Der, C. J., & Sondek, J. (2005). GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nature Reviews. Molecular Cell Biology, 6(2), 167–180.

    Article  PubMed  CAS  Google Scholar 

  38. Bernards, A., & Settleman, J. (2004). GAP control: regulating the regulators of small GTPases. Trends in Cell Biology, 14(7), 377–385.

    Article  PubMed  CAS  Google Scholar 

  39. Tcherkezian, J., & Lamarche-Vane, N. (2007). Current knowledge of the large RhoGAP family of proteins. Biology of the Cell, 99(2), 67–86.

    Article  PubMed  CAS  Google Scholar 

  40. Kandpal, R. P. (2006). Rho GTPase activating proteins in cancer phenotypes. Current Protein & Peptide Science, 7(4), 355–365.

    Article  CAS  Google Scholar 

  41. Chang, J. H., Gill, S., Settleman, J., & Parsons, S. J. (1995). c-Src regulates the simultaneous rearrangement of actin cytoskeleton, p190RhoGAP, and p120RasGAP following epidermal growth factor stimulation. Journal of Cell Biology, 130(2), 355–368.

    Article  PubMed  CAS  Google Scholar 

  42. Xue, W., Krasnitz, A., Lucito, R., Sordella, R., Vanaelst, L., Cordon-Cardo, C., et al. (2008). DLC1 is a chromosome 8p tumor suppressor whose loss promotes hepatocellular carcinoma. Genes & Development, 22(11), 1439–1444.

    Article  CAS  Google Scholar 

  43. Sjoblom, T., Jones, S., Wood, L. D., Parsons, D. W., Lin, J., Barber, T. D., et al. (2006). The consensus coding sequences of human breast and colorectal cancers. Science, 314(5797), 268–274.

    Article  PubMed  Google Scholar 

  44. Jones, S., Zhang, X., Parsons, D. W., Lin, J. C., Leary, R. J., Angenendt, P., et al. (2008). Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science, 321(5897), 1801–1806.

    Article  PubMed  CAS  Google Scholar 

  45. Yuan, B. Z., Jefferson, A. M., Baldwin, K. T., Thorgeirsson, S. S., Popescu, N. C., & Reynolds, S. H. (2004). DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas. Oncogene, 23(7), 1405–1411.

    Article  PubMed  CAS  Google Scholar 

  46. Yuan, B. Z., Zhou, X., Durkin, M. E., Zimonjic, D. B., Gumundsdottir, K., Eyfjord, J. E., et al. (2003). DLC-1 gene inhibits human breast cancer cell growth and in vivo tumorigenicity. Oncogene, 22(3), 445–450.

    Article  PubMed  CAS  Google Scholar 

  47. Zhou, X., Thorgeirsson, S. S., & Popescu, N. C. (2004). Restoration of DLC-1 gene expression induces apoptosis and inhibits both cell growth and tumorigenicity in human hepatocellular carcinoma cells. Oncogene, 23(6), 1308–1313.

    Article  PubMed  CAS  Google Scholar 

  48. Healy, K. D., Hodgson, L., Kim, T. Y., Shutes, A., Maddileti, S., Juliano, R. L., et al. (2008). DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms. Molecular Carcinogenesis, 47(5), 326–337.

    Article  PubMed  CAS  Google Scholar 

  49. Li, H., Fung, K. L., Jin, D. Y., Chung, S. S., Ching, Y. P., Ng, I. O., et al. (2007). Solution structures, dynamics, and lipid-binding of the sterile alpha-motif domain of the deleted in liver cancer 2. Proteins, 67(4), 1154–1166.

    Article  PubMed  CAS  Google Scholar 

  50. Kim, T. Y., Healy, K. D., Der, C. J., Sciaky, N., Bang, Y. J., Juliano, R. L. (2008). Effects of structure of Rho GTPase-activating protein DLC-1 on cell morphology and migration. Journal of Biological Chemistry, [epub ahead of print] http://www.jbc.org/cgi/reprint/M800617200v800617201.

  51. Liao, Y. C., Si, L., deVere White, R. W., & Lo, S. H. (2007). The phosphotyrosine-independent interaction of DLC-1 and the SH2 domain of cten regulates focal adhesion localization and growth suppression activity of DLC-1. Journal of Cell Biology, 176(1), 43–49.

    Article  PubMed  CAS  Google Scholar 

  52. Qian, X., Li, G., Asmussen, H. K., Asnaghi, L., Vass, W. C., Braverman, R., et al. (2007). Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities. Proceedings of the National Academy of Sciences of the United States of America, 104(21), 9012–9017.

    Article  PubMed  CAS  Google Scholar 

  53. Gay, N. J., & Keith, F. J. (1991). Drosophila Toll and IL-1 receptor. Nature, 351(6325), 355–356.

    Article  PubMed  CAS  Google Scholar 

  54. Zhou, X., Zimonjic, D. B., Park, S. W., Yang, X. Y., Durkin, M. E., & Popescu, N. C. (2008). DLC1 suppresses distant dissemination of human hepatocellular carcinoma cells in nude mice through reduction of RhoA GTPase activity, actin cytoskeletal disruption and down-regulation of genes involved in metastasis. International Journal of Oncology, 32(6), 1285–1291.

    PubMed  CAS  Google Scholar 

  55. Kang, Y., Siegel, P. M., Shu, W., Drobnjak, M., Kakonen, S. M., Cordon-Cardo, C., et al. (2003). A multigenic program mediating breast cancer metastasis to bone. Cancer Cell, 3(6), 537–549.

    Article  PubMed  CAS  Google Scholar 

  56. Kim, T. Y., Lee, J. W., Kim, H. P., Jong, H. S., Kim, T. Y., Jung, M., et al. (2007). DLC-1, a GTPase-activating protein for Rho, is associated with cell proliferation, morphology, and migration in human hepatocellular carcinoma. Biochemical and Biophysical Research Communications, 355(1), 72–77.

    Article  PubMed  CAS  Google Scholar 

  57. Syed, V., Mukherjee, K., Lyons-Weiler, J., Lau, K. M., Mashima, T., Tsuruo, T., et al. (2005). Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling. Oncogene, 24(10), 1774–1787.

    Article  PubMed  CAS  Google Scholar 

  58. Wong, C. M., Yam, J. W., Ching, Y. P., Yau, T. O., Leung, T. H., Jin, D. Y., et al. (2005). Rho GTPase-activating protein deleted in liver cancer suppresses cell proliferation and invasion in hepatocellular carcinoma. Cancer Research, 65(19), 8861–8868.

    Article  PubMed  CAS  Google Scholar 

  59. Euer, N., Schwirzke, M., Evtimova, V., Burtscher, H., Jarsch, M., Tarin, D., et al. (2002). Identification of genes associated with metastasis of mammary carcinoma in metastatic versus non-metastatic cell lines. Anticancer Research, 22(2A), 733–740.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA

    T. Y. Kim, D. Vigil, C. J. Der & R. L. Juliano

  2. Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA

    T. Y. Kim, D. Vigil, C. J. Der & R. L. Juliano

Authors
  1. T. Y. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Vigil
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. J. Der
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. L. Juliano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. L. Juliano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, T.Y., Vigil, D., Der, C.J. et al. Role of DLC-1, a tumor suppressor protein with RhoGAP activity, in regulation of the cytoskeleton and cell motility. Cancer Metastasis Rev 28, 77–83 (2009). https://doi.org/10.1007/s10555-008-9167-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-008-9167-2

Keywords

Search

Navigation