Skip to main content
SpringerLink
Log in

Rho Proteins and Cancer

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The Rho family of GTPases has been intensively studied for their roles in signal transduction processes leading to cytoskeletal-dependent responses, including cell migration and phagocytosis. In addition, they are important regulators of cell cycle progression and affect the expression of a number of genes, including those for matrix-degrading proteases implicated in cancer invasion. So far, the expression of some Rho family members has been found to be increased in some human cancers, and some cancer-associated mutations in Rho family regulators have been characterized. This makes Rho protein signalling pathways attractive targets for cancer therapy. However, there is little evidence so far from animal studies to define if and how Rho proteins contribute to cancer cell proliferation, survival, invasion and metastasis.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ridley AJ: Rho GTPases and cell migration. J Cell Sci 114: 2713–2722, 2001

    Google Scholar 

  2. Etienne-Manneville S, Hall A: Rho GTPases in cell biology. Nature 420: 629–635, 2002

    Google Scholar 

  3. Clark EA, Golub TR, Lander ES, Hynes RO: Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406: 532–535, 2000

    Google Scholar 

  4. Itoh K, Yoshioka K, Akedo H, UehataM, Ishizaki T, Narumiya S: An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nat Med 5: 221–225, 1999

    Google Scholar 

  5. Jaffe AB, Hall A: Rho GTPases in transformation and metastasis. Adv Cancer Res 84: 57–80, 2002

    Google Scholar 

  6. Sahai E, Marshall CJ: Rho-GTPases and Cancer. Nat Rev Cancer 2: 133–142, 2002

    Google Scholar 

  7. Price LS, Collard JG: Regulation of the cytoskeleton by Rhofamily GTPases: implications for tumour cell invasion. Semin Cancer Biol 11: 167–173, 2001

    Google Scholar 

  8. Mareel M, Leroy A: Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev 83: 337–376, 2003

    Google Scholar 

  9. Engers R, Springer E, Michiels F, Collard JG, Gabbert HE: Rac affects invasion of human renal cell carcinomas by upregulating tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 expression. J Biol Chem 276: 41889–41897, 2001

    Google Scholar 

  10. Soon LL, Yie TA, Shvarts A, Levine AJ, Su F, Tchou-Wong KM: Overexpression of WISP-1 down-regulated motility and invasion of lung cancer cells through inhibition of Rac activation. J Biol Chem 278: 11465–11470, 2003

    Google Scholar 

  11. Zhuge Y, Xu J: Rac1 mediates type I collagen-dependent MMP-2 activation. Role in cell invasion across collagen barrier. J Biol Chem 276: 16248–16256, 2001

    Google Scholar 

  12. Kheradmand F, Werner E, Tremble P, Symons M, Werb Z: Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. Science 280: 898–902, 1998

    Google Scholar 

  13. Cho SY, Klemke RL: Extracellular-regulated kinase activation and CAS/Crk coupling regulate cell migration and suppress apoptosis during invasion of the extracellular matrix. J Cell Biol 149: 223–236, 2000

    Google Scholar 

  14. Ozanne BW, McGarry L, Spence HJ, Johnston I, Winnie J, Meagher L, Stapleton G: Transcriptional regulation of cell invasion: AP-1 regulation of a multigenic invasion programme. Eur J Cancer 36: 1640–1648, 2000

    Google Scholar 

  15. Evers EE, Zondag GC, Malliri A, Price LS, ten Klooster JP, van der Kammen RA, Collard JG: Rho family proteins in cell adhesion and cell migration. Eur J Cancer 36: 1269–1274, 2000

    Google Scholar 

  16. Ridley AJ, Comoglio PM, Hall A: Regulation of scatter factor/hepatocyte growth factor responses by Ras, Rac, and Rho in MDCK cells. Mol Cell Biol 15: 1110–1122, 1995

    Google Scholar 

  17. Lamorte L, Rodrigues S, Naujokas M, Park M: Crk synergizes with epidermal growth factor for epithelial invasion and morphogenesis and is required for the met morphogenic program. J Biol Chem 277: 37904–37911, 2002

    Google Scholar 

  18. Evan G, Littlewood T: A matter of life and cell death. Science 281: 1317–1322, 1998 19. Green DR, Evan GI: A matter of life and death. Cancer Cell 1: 19–30, 2002

    Google Scholar 

  19. Aznar S, Lacal JC: Rho signals to cell growth and apoptosis. Cancer Lett 165: 1–10, 2001

    Google Scholar 

  20. Xu Z, Kukekov NV, Greene LA: POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis. Embo J 22: 252–261, 2003

    Google Scholar 

  21. Leverrier Y, Ridley AJ: Apoptosis: caspases orchestrate the ROCK ‘n’ bleb. Nat Cell Biol 3: E91-E93, 2001

    Google Scholar 

  22. Obaya AJ, Sedivy JM: Regulation of cyclin-Cdk activity in mammalian cells. Cell Mol Life Sci 59: 126–142, 2002

    Google Scholar 

  23. Ortega S, Malumbres M, Barbacid M: Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta 1602: 73–87, 2002

    Google Scholar 

  24. Liberto M, Cobrinik D, Minden A: Rho regulates p21(CIP1), cyclin D1, and checkpoint control inmammary epithelial cells. Oncogene 21: 1590–1599, 2002

    Google Scholar 

  25. Sahai E, Olson MF, Marshall CJ: Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility. Embo J 20: 755–766, 2001

    Google Scholar 

  26. Tanaka H, Yamashita T, Asada M, Mizutani S, Yoshikawa H, Tohyama M: Cytoplasmic p21(Cip1/WAF1) regulates neurite remodeling by inhibiting Rho-kinase activity. J Cell Biol 158: 321–329, 2002

    Google Scholar 

  27. Joyce D, Bouzahzah B, Fu M, Albanese C, D'Amico M, Steer J, Klein JU, Lee RJ, Segall JE, Westwick JK, Der CJ, Pestell RG: Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-κB-dependent pathway. J Biol Chem 274: 25245–25249, 1999

    Google Scholar 

  28. Malliri A, van der Kammen RA, Clark K, van der Valk M, Michiels F, Collard JG: Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417: 867–871, 2002

    Google Scholar 

  29. Preudhomme C, Roumier C, Hildebrand MP, Dallery-Prudhomme E, Lantoine D, Lai JL, Daudignon A, Adenis C, Bauters F, Fenaux P, Kerckaert JP, Galiegue-Zouitina S: Nonrandom 4p13 rearrangements of the RhoH/TTF gene, encoding a GTP-binding protein, in non-Hodgkin's lymphoma and multiple myeloma. Oncogene 19: 2023–2032, 2000

    Google Scholar 

  30. Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, Kuppers R, Dalla-Favera R: Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412: 341–346, 2001

    Google Scholar 

  31. Li X, Bu X, Lu B, Avraham H, Flavell RA, Lim B: The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol Cell Biol 22: 1158–1171, 2002

    Google Scholar 

  32. Peck J, Douglas Gt, Wu CH, Burbelo PD: Human RhoGAP domain-containing proteins: structure, function and evolutionary relationships. FEBS Lett 528: 27–34, 2002

    Google Scholar 

  33. Kourlas PJ, Strout MP, Becknell B, Veronese ML, Croce CM, Theil KS, Krahe R, Ruutu T, Knuutila S, Bloomfield CD, Caligiuri MA: Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: evidence for its fusion with MLL in acute myeloid leukemia. Proc Natl Acad Sci USA 97: 2145–2150, 2000

    Google Scholar 

  34. Ernst P, Wang J, Korsmeyer SJ: The role of MLL in hematopoiesis and leukemia. Curr Opin Hematol 9: 282–287, 2002

    Google Scholar 

  35. Kuner R, Swiercz JM, Zywietz A, Tappe A, Offermanns S: Characterization of the expression of PDZ-RhoGEF, LARG and Gá12/Gá13 proteins in the murine nervous system. Eur J Neurosci 16: 2333–2341, 2002

    Google Scholar 

  36. Swiercz JM, Kuner R, Behrens J, Offermanns S: Plexin-B1 directly interacts with PDZ-RhoGEF/LARG to regulate RhoA and growth cone morphology. Neuron 35: 51–63, 2002

    Google Scholar 

  37. Perrot V, Vazquez-Prado J, Gutkind JS: Plexin B regulates Rho through the guanine nucleotide exchange factors leukemiaassociated Rho GEF (LARG) and PDZ-RhoGEF. J Biol Chem 277: 43115–43120, 2002

    Google Scholar 

  38. Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, Tamagnone L, Comoglio PM: The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol 4: 720–724, 2002

    Google Scholar 

  39. Trusolino L, Comoglio PM: Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2: 289–300, 2002

    Google Scholar 

  40. Engers R, Zwaka TP, Gohr L, Weber A, Gerharz CD, Gabbert HE: Tiam1 mutations in human renal-cell carcinomas. Int J Cancer 88: 369–376, 2000

    Google Scholar 

  41. Arlinghaus RB: Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia. Oncogene 21: 8560–8567, 2002

    Google Scholar 

  42. Noren NK, Arthur WT, Burridge K: Cadherin engagement inhibits RhoA via p190RhoGAP. J Biol Chem 278: 13615–13618, 2003

    Google Scholar 

  43. Tsubouchi A, Sakakura J, Yagi R, Mazaki Y, Schaefer E, Yano H, Sabe H: Localized suppression of RhoA activity by Tyr31/118-phosphorylated paxillin in cell adhesion and migration. J Cell Biol 159: 673–683, 2002

    Google Scholar 

  44. Wolf RM, Draghi N, Liang X, Dai C, Uhrbom L, Eklof C, Westermark B, Holland EC, Resh MD: p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor suppressor encoded on human chromosome 19q13.3. Genes Dev 17: 476–487, 2003

    Google Scholar 

  45. Sordella R, Classon M, Hu KQ, Matheson SF, Brouns MR, Fine B, Zhang L, Takami H, Yamada Y, Settleman J: Modulation of CREB activity by the Rho GTPase regulates cell and organism size during mouse embryonic development. Dev Cell 2: 553–565, 2002

    Google Scholar 

  46. Ching YP, Wong CM, Chan SF, Leung TH, Ng DC, Jin DY, Ng IO: Deleted in Liver Cancer (DLC) 2 Encodes a RhoGAP Protein with Growth Suppressor Function and Is Underexpressed in Hepatocellular Carcinoma. J Biol Chem 278: 10824–10830, 2003

    Google Scholar 

  47. Mira JP, Benard V, Groffen J, Sanders LC, Knaus UG: Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated kinase-dependent pathway. Proc Natl Acad Sci USA 97: 185–189, 2000

    Google Scholar 

  48. Ahn SJ, Chung KW, Lee RA, Park IA, Lee SH, Park DE, Noh DY: Overexpression of âPix-a in human breast cancer tissues. Cancer Lett 193: 99–107, 2003

    Google Scholar 

  49. Hornstein I, Pikarsky E, Groysman M, Amir G, Peylan-Ramu N, Katzav S: The haematopoietic specific signal transducer Vav1 is expressed in a subset of human neuroblastomas. J Pathol 199: 526–533, 2003

    Google Scholar 

  50. Kumar R, Vadlamudi RK: Emerging functions of p21-activated kinases in human cancer cells. J Cell Physiol 193: 133–144, 2002

    Google Scholar 

  51. Wang W, Wyckoff JB, Frohlich VC, Oleynikov Y, Huttelmaier S, Zavadil J, Cermak L, Bottinger EP, Singer RH, White JG, Segall JE, Condeelis JS: Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res 62: 6278–6288, 2002

    Google Scholar 

  52. Somlyo AV, Bradshaw D, Ramos S, Murphy C, Myers CE, Somlyo AP: Rho-kinase inhibitor retards migration and in vivo dissemination of human prostate cancer cells. Biochem Biophys Res Commun 269: 652–659, 2000

    Google Scholar 

  53. Lefer AM, Scalia R, Lefer DJ: Vascular effects of HMG CoAreductase inhibitors (statins) unrelated to cholesterol lowering: new concepts for cardiovascular disease. Cardiovasc Res 49: 281–287, 2001

    Google Scholar 

  54. Takemoto M, Liao JK: Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 21: 1712–1719, 2001

    Google Scholar 

  55. Wong WW, Dimitroulakos J, Minden MD, Penn LZ: HMGCoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia 16: 508–519, 2002

    Google Scholar 

  56. Haluska P, Dy GK, Adjei AA: Farnesyl transferase inhibitors as anticancer agents. Eur J Cancer 38: 1685–1700, 2002

    Google Scholar 

  57. Prendergast GC: ‘Actin’ up: RhoB in cancer and apoptosis. Nat Rev Cancer 1: 162–168, 2001

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Ludwig Institute for Cancer Research, Royal Free and University College School of Medicine, University College London, London, UK

    Anne J. Ridley

Authors
  1. Anne J. Ridley
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ridley, A.J. Rho Proteins and Cancer. Breast Cancer Res Treat 84, 13–19 (2004). https://doi.org/10.1023/B:BREA.0000018423.47497.c6

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:BREA.0000018423.47497.c6

Search

Navigation