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Rho GTPases in Regulation of Cancer Cell Motility, Invasion, and Microenvironment

  • Donita C. Brady
  • Jamie K. Alan
  • Adrienne D. Cox
Chapter
Part of the Cancer Genetics book series (CANGENETICS)

Abstract

Unlike Ras proteins that are oncogenically mutated in 30% of human cancers, known naturally occurring mutations in Rho GTPases are limited to RhoH (a.k.a. ARHH). This gene has been found to be rearranged in non-Hodgkin’s lymphomas and multiple myeloma, along with mutations in the 5UTR in diffuse large cell lymphomas (Preudhomme et al. 2000; Pasqualucci et al. 2001). The common rearrangement found in these hematopoietic cancers is caused by a t(3;4)(q27; p11–13) chromosomal translocation resulting in a gene fusion with the BCL3/LAZ3 oncogene (Dallery-Prudhomme et al. 1997). How these RhoH translocations and hypermutations – as well as other aberrantly expressed Rho GTPases – contribute to the cancer pathogenesis remains an open question. However, a large body of evidence points to their involvement in EMT.

Keywords

Actin Polymerization Small GTPases Adherens Junction Squamous Cell Carcinoma Cell Cdc42 Activation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Adam L, Vadlamudi RK, McCrea P, Kumar R (2001) Tiam1 overexpression potentiates heregulin-induced lymphoid enhancer factor-1/beta-catenin nuclear signaling in breast cancer cells by modulating the intercellular stability. J Biol Chem 276:28443–28450.PubMedCrossRefGoogle Scholar
  2. Ahn SJ, Chung KW, Lee RA, Park IA, Lee SH, Park DE, Noh DY (2003) Overexpression of betaPix-a in human breast cancer tissues. Cancer Lett 193:99–107.PubMedCrossRefGoogle Scholar
  3. Akhtar N and Hotchin NA (2001) RAC1 regulates adherens junctions through endocytosis of E-cadherin. Mol Biol Cell 12:847–862.PubMedGoogle Scholar
  4. Allen WE, Jones GE, Pollard JW, Ridley AJ (1997) Rho, Rac and Cdc42 regulate actin organization and cell adhesion in macrophages. J Cell Sci 110 (Pt 6):707–720.PubMedGoogle Scholar
  5. Allen WE, Zicha D, Ridley AJ, Jones GE (1998) A role for Cdc42 in macrophage chemotaxis. J Cell Biol 141:1147–1157.PubMedCrossRefGoogle Scholar
  6. Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K (1996) Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem 271:20246–20249.PubMedCrossRefGoogle Scholar
  7. Arlinghaus RB (2002) Bcr: A negative regulator of the Bcr-Abl oncoprotein in leukemia. Oncogene 21:8560–8567.PubMedCrossRefGoogle Scholar
  8. Aspenstrom P, Ruusala A, Pacholsky D (2007) Taking Rho GTPases to the next level: The cellular functions of atypical Rho GTPases. Exp Cell Res 313:3673–3679.PubMedCrossRefGoogle Scholar
  9. Bailly M, Ichetovkin I, Grant W, Zebda N, Machesky LM, Segall JE, Condeelis J (2001) The F-actin side binding activity of the Arp2/3 complex is essential for actin nucleation and lamellipod extension. Curr Biol 11:620–625.PubMedCrossRefGoogle Scholar
  10. Bamburg JR, McGough A, Ono S (1999) Putting a new twist on actin: ADF/cofilins modulate actin dynamics. Trends Cell Biol 9:364–370.PubMedCrossRefGoogle Scholar
  11. Bartolome RA, Molina-Ortiz I, Samaniego R, Sanchez-Mateos P, Bustelo XR, Teixido J (2006) Activation of Vav/Rho GTPase signaling by CXCL12 controls membrane-type matrix metalloproteinase-dependent melanoma cell invasion. Cancer Res 66:248–258.PubMedCrossRefGoogle Scholar
  12. Bellovin DI, Simpson KJ, Danilov T, Maynard E, Rimm DL, Oettgen P, Mercurio AM (2006) Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma. Oncogene 25:6959–6967.PubMedCrossRefGoogle Scholar
  13. Bernards A (2003) GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. Biochim Biophys Acta 1603:47–82.PubMedGoogle Scholar
  14. Berx G, Raspe E, Christofori G, Thiery JP, Sleeman JP (2007) Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer. Clin Exp Metastasis 24:587–597.PubMedCrossRefGoogle Scholar
  15. Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, Moses HL (2001) Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 12:27–36.PubMedGoogle Scholar
  16. Birchmeier W and Behrens J (1994) Cadherin expression in carcinomas: Role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta 1198:11–26.PubMedGoogle Scholar
  17. Bishop AL and Hall A (2000) Rho GTPases and their effector proteins. Biochem J 348 Pt 2:241–255.Google Scholar
  18. Bos JL (1989) ras oncogenes in human cancer: A review. Cancer Res 49:4682–4689.PubMedGoogle Scholar
  19. Boureux A, Vignal E, Faure S, Fort P (2007) Evolution of the Rho family of ras-like GTPases in eukaryotes. Mol Biol Evol 24:203–216.PubMedCrossRefGoogle Scholar
  20. Bracke ME, Van Roy FM, Mareel MM (1996) The E-cadherin/catenin complex in invasion and metastasis. Curr Top Microbiol Immunol 213 (Pt 1):123–161.PubMedGoogle Scholar
  21. Braga VM, Betson M, Li X, Lamarche-Vane N (2000) Activation of the small GTPase Rac is sufficient to disrupt cadherin-dependent cell-cell adhesion in normal human keratinocytes. Mol Biol Cell 11:3703–3721.PubMedGoogle Scholar
  22. Braga VM, Del Maschio A, Machesky L, Dejana E (1999) Regulation of cadherin function by Rho and Rac: Modulation by junction maturation and cellular context. Mol Biol Cell 10:9–22.PubMedGoogle Scholar
  23. Braga VM, Machesky LM, Hall A, Hotchin NA (1997) The small GTPases Rho and Rac are required for the establishment of cadherin-dependent cell-cell contacts. J Cell Biol 137:1421–1431.PubMedCrossRefGoogle Scholar
  24. Bresnick AR (1999) Molecular mechanisms of nonmuscle myosin-II regulation. Curr Opin Cell Biol 11:26–33.PubMedCrossRefGoogle Scholar
  25. Chardin P (2006) Function and regulation of Rnd proteins. Nat Rev Mol Cell Biol 7:54–62.PubMedCrossRefGoogle Scholar
  26. Chien UH, Lai M, Shih TY, Verma IM, Scolnick EM, Roy-Burman P, Davidson N (1979) Heteroduplex analysis of the sequence relationships between the genomes of Kirsten and Harvey sarcoma viruses, their respective parental murine leukemia viruses, and the rat endogenous 30S RNA. J Virol 31:752–760.PubMedGoogle Scholar
  27. Ching YP, Wong CM, Chan SF, Leung TH, Ng DC, Jin DY, Ng IO (2003) 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.PubMedCrossRefGoogle Scholar
  28. Chuang TH, Bohl BP, Bokoch GM (1993) Biologically active lipids are regulators of Rac.GDI complexation. J Biol Chem 268:26206–26211.PubMedGoogle Scholar
  29. Clark EA, Golub TR, Lander ES, Hynes RO (2000) Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406:532–535.PubMedCrossRefGoogle Scholar
  30. Condeelis J (2001) How is actin polymerization nucleated in vivo? Trends Cell Biol 11:288–293.PubMedCrossRefGoogle Scholar
  31. Cote JF and Vuori K (2007) GEF what? Dock180 and related proteins help Rac to polarize cells in new ways. Trends Cell Biol 17:383–393.PubMedCrossRefGoogle Scholar
  32. Cotteret S and Chernoff J (2002) The evolutionary history of effectors downstream of Cdc42 and Rac. Genome Biol 3:REVIEWS0002–8.PubMedCrossRefGoogle Scholar
  33. Cox EA and Huttenlocher A (1998) Regulation of integrin-mediated adhesion during cell migration. Microsc Res Tech 43:412–419.PubMedCrossRefGoogle Scholar
  34. Cox EA, Sastry SK, Huttenlocher A (2001) Integrin-mediated adhesion regulates cell polarity and membrane protrusion through the Rho family of GTPases. Mol Biol Cell 12:265–277.PubMedGoogle Scholar
  35. Dallery-Prudhomme E, Roumier C, Denis C, Preudhomme C, Kerckaert JP, Galiegue-Zouitina S (1997) Genomic structure and assignment of the RhoH/TTF small GTPase gene (ARHH) to 4p13 by in situ hybridization. Genomics 43:89–94.PubMedCrossRefGoogle Scholar
  36. Der CJ, Krontiris TG, Cooper GM (1982) Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc Natl Acad Sci U S A 79:3637–3640.PubMedCrossRefGoogle Scholar
  37. DerMardirossian C and Bokoch GM (2005) GDIs: Central regulatory molecules in Rho GTPase activation. Trends Cell Biol 15:356–363.PubMedCrossRefGoogle Scholar
  38. Dovas A and Couchman JR (2005) RhoGDI: Multiple functions in the regulation of Rho family GTPase activities. Biochem J 390:1–9.PubMedCrossRefGoogle Scholar
  39. Edwards DC, Sanders LC, Bokoch GM, Gill GN (1999) Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat Cell Biol 1:253–259.PubMedCrossRefGoogle Scholar
  40. Ellenbroek SI and Collard JG (2007) Rho GTPases: Functions and association with cancer. Clin Exp Metastasis 24:657–672.PubMedCrossRefGoogle Scholar
  41. Engers R, Mueller M, Walter A, Collard JG, Willers R, Gabbert HE (2006) Prognostic relevance of Tiam1 protein expression in prostate carcinomas. Br J Cancer 95:1081–1086.PubMedCrossRefGoogle Scholar
  42. Esufali S, Charames GS, Pethe VV, Buongiorno P, Bapat B (2007) Activation of tumor-specific splice variant Rac1b by dishevelled promotes canonical Wnt signaling and decreased adhesion of colorectal cancer cells. Cancer Res 67:2469–2479.PubMedCrossRefGoogle Scholar
  43. Etienne-Manneville S (2004) Cdc42 – The centre of polarity. J Cell Sci 117:1291–1300.PubMedCrossRefGoogle Scholar
  44. Etienne-Manneville S and Hall A (2001) Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCzeta. Cell 106:489–498.PubMedCrossRefGoogle Scholar
  45. Etienne-Manneville S and Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635.PubMedCrossRefGoogle Scholar
  46. Etienne-Manneville S and Hall A (2003) Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity. Nature 421:753–756.PubMedCrossRefGoogle Scholar
  47. Evers EE, Zondag GC, Malliri A, Price LS, ten Klooster JP, van der Kammen RA, Collard JG (2000) Rho family proteins in cell adhesion and cell migration. Eur J Cancer 36:1269–1274.PubMedCrossRefGoogle Scholar
  48. Fang WB, Ireton RC, Zhuang G, Takahashi T, Reynolds A, Chen J (2008) Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism. J Cell Sci 121:358–368.PubMedCrossRefGoogle Scholar
  49. Fernandez-Zapico ME, Gonzalez-Paz NC, Weiss E, Savoy DN, Molina JR, Fonseca R, Smyrk TC, Chari ST, Urrutia R, Billadeau DD (2005) Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis. Cancer Cell 7:39–49.PubMedCrossRefGoogle Scholar
  50. Foster R, Hu KQ, Lu Y, Nolan KM, Thissen J, Settleman J (1996) Identification of a novel human Rho protein with unusual properties: GTPase deficiency and in vivo farnesylation. Mol Cell Biol 16:2689–2699.PubMedGoogle Scholar
  51. Friedl P, Wolf K (2003) Tumour-cell invasion and migration: Diversity and escape mechanisms. Nat Rev Cancer 3:362–374.PubMedCrossRefGoogle Scholar
  52. Fukumoto Y, Kaibuchi K, Hori Y, Fujioka H, Araki S, Ueda T, Kikuchi A, Takai Y (1990) Molecular cloning and characterization of a novel type of regulatory protein (GDI) for the rho proteins, ras p21-like small GTP-binding proteins. Oncogene 5:1321–1328.PubMedGoogle Scholar
  53. Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, Sahai E (2007) Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol 9:1392–1400.PubMedCrossRefGoogle Scholar
  54. Guarino M, Rubino B, Ballabio G (2007) The role of epithelial-mesenchymal transition in cancer pathology. Pathology 39:305–318.PubMedCrossRefGoogle Scholar
  55. Gumbiner B, Stevenson B, Grimaldi A (1988) The role of the cell adhesion molecule uvomorulin in the formation and maintenance of the epithelial junctional complex. J Cell Biol 107:1575–1587.PubMedCrossRefGoogle Scholar
  56. Gupton SL, Eisenmann K, Alberts AS, Waterman-Storer CM (2007) mDia2 regulates actin and focal adhesion dynamics and organization in the lamella for efficient epithelial cell migration. J Cell Sci 120:3475–3487.PubMedCrossRefGoogle Scholar
  57. Hakem A, Sanchez-Sweatman O, You-Ten A, Duncan G, Wakeham A, Khokha R, Mak TW (2005) RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis. Genes Dev 19:1974–1979.PubMedCrossRefGoogle Scholar
  58. Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279:509–514.PubMedCrossRefGoogle Scholar
  59. Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70.PubMedCrossRefGoogle Scholar
  60. Healy KD, Hodgson L, Kim TY, Shutes A, Maddileti S, Juliano RL, Hahn KM, Harden TK, Bang YJ, Der CJ (2007) DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms. Mol Carcinog 47:326–337.Google Scholar
  61. Hoffman GR, Nassar N, Cerione RA (2000) Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI. Cell 100:345–356.PubMedCrossRefGoogle Scholar
  62. Hordijk PL, ten Klooster JP, van der Kammen RA, Michiels F, Oomen LC, Collard JG (1997) Inhibition of invasion of epithelial cells by Tiam1-Rac signaling. Science 278:1464–1466.PubMedCrossRefGoogle Scholar
  63. Hornstein I, Pikarsky E, Groysman M, Amir G, Peylan-Ramu N, Katzav S (2003) The haematopoietic specific signal transducer Vav1 is expressed in a subset of human neuroblastomas. J Pathol 199:526–533.PubMedCrossRefGoogle Scholar
  64. Hotulainen P and Lappalainen P (2006) Stress fibers are generated by two distinct actin assembly mechanisms in motile cells. J Cell Biol 173:383–394.PubMedCrossRefGoogle Scholar
  65. Ikoma T, Takahashi T, Nagano S, Li YM, Ohno Y, Ando K, Fujiwara T, Fujiwara H, Kosai K (2004) A definitive role of RhoC in metastasis of orthotopic lung cancer in mice. Clin Cancer Res 10:1192–1200.PubMedCrossRefGoogle Scholar
  66. Itoh K, Yoshioka K, Akedo H, Uehata M, Ishizaki T, Narumiya S (1999) An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nat Med 5:221–225.PubMedCrossRefGoogle Scholar
  67. Jordan P, Brazao R, Boavida MG, Gespach C, Chastre E (1999) Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors. Oncogene 18:6835–6839.PubMedCrossRefGoogle Scholar
  68. Kamai T, Tsujii T, Arai K, Takagi K, Asami H, Ito Y, Oshima H (2003) Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res 9:2632–2641.PubMedGoogle Scholar
  69. Kamai T, Yamanishi T, Shirataki H, Takagi K, Asami H, Ito Y, Yoshida K (2004) Overexpression of RhoA, Rac1, and Cdc42 GTPases is associated with progression in testicular cancer. Clin Cancer Res 10:4799–4805.PubMedCrossRefGoogle Scholar
  70. Kawano Y, Fukata Y, Oshiro N, Amano M, Nakamura T, Ito M, Matsumura F, Inagaki M, Kaibuchi K (1999) Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo. J Cell Biol 147:1023–1038.PubMedCrossRefGoogle Scholar
  71. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K (1996) Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273:245–248.PubMedCrossRefGoogle Scholar
  72. Kin Y, Li G, Shibuya M, Maru Y (2001) The Dbl homology domain of BCR is not a simple spacer in P210BCR-ABL of the Philadelphia chromosome. J Biol Chem 276:39462–39468.PubMedCrossRefGoogle Scholar
  73. Kourlas PJ, Strout MP, Becknell B, Veronese ML, Croce CM, Theil KS, Krahe R, Ruutu T, Knuutila S, Bloomfield CD, Caligiuri MA (2000) 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 U S A 97:2145–2150.PubMedCrossRefGoogle Scholar
  74. Kozma R, Ahmed S, Best A, Lim L (1995) The Ras-related protein Cdc42Hs and bradykinin promote formation of peripheral actin microspikes and filopodia in Swiss 3T3 fibroblasts. Mol Cell Biol 15:1942–1952.PubMedGoogle Scholar
  75. Kumar R and Vadlamudi RK (2002) Emerging functions of p21-activated kinases in human cancer cells. J Cell Physiol 193:133–144.PubMedCrossRefGoogle Scholar
  76. Lamarche N and Hall A (1994) GAPs for rho-related GTPases. Trends Genet 10:436–440.PubMedCrossRefGoogle Scholar
  77. Lee EY, Parry G, Bissell MJ (1984) Modulation of secreted proteins of mouse mammary epithelial cells by the collagenous substrata. J Cell Biol 98:146–155.PubMedCrossRefGoogle Scholar
  78. Li X, Bu X, Lu B, Avraham H, Flavell RA, Lim B (2002) 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.PubMedCrossRefGoogle Scholar
  79. Liotta LA and Kohn EC (2001) The microenvironment of the tumour-host interface. Nature 411:375–379.PubMedCrossRefGoogle Scholar
  80. Liu N, Bi F, Pan YL, Xue Y, Han ZY, Liu CJ, Fan DM (2004) [Expression of RhoC in gastric cancer cell lines and construction and identification of RhoC-specific siRNA expression vector]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 20:148–151.PubMedGoogle Scholar
  81. Lozano E, Betson M, Braga VM (2003) Tumor progression: Small GTPases and loss of cell-cell adhesion. Bioessays 25:452–463.PubMedCrossRefGoogle Scholar
  82. Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S (1999) Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285:895–898.PubMedCrossRefGoogle Scholar
  83. Malliri A and Collard JG (2003) Role of Rho-family proteins in cell adhesion and cancer. Curr Opin Cell Biol 15:583–589.PubMedCrossRefGoogle Scholar
  84. Malliri A, van der Kammen RA, Clark K, van der Valk M, Michiels F, Collard JG (2002) Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417:867–871.PubMedCrossRefGoogle Scholar
  85. Matos P and Jordan P (2005) Expression of Rac1b stimulates NF-kappaB-mediated cell survival and G1/S progression. Exp Cell Res 305:292–299.PubMedCrossRefGoogle Scholar
  86. Matsumoto Y, Tanaka K, Harimaya K, Nakatani F, Matsuda S, Iwamoto Y (2001) Small GTP-binding protein, Rho, both increased and decreased cellular motility, activation of matrix metalloproteinase 2 and invasion of human osteosarcoma cells. Jpn J Cancer Res 92:429–438.PubMedGoogle Scholar
  87. Meller N, Merlot S, Guda C (2005) CZH proteins: A new family of Rho-GEFs. J Cell Sci 118:4937–4946.PubMedCrossRefGoogle Scholar
  88. Michaelson D, Silletti J, Murphy G, D’Eustachio P, Rush M, Philips MR (2001) Differential localization of Rho GTPases in live cells: Regulation by hypervariable regions and RhoGDI binding. J Cell Biol 152:111–126.PubMedCrossRefGoogle Scholar
  89. Miki H, Yamaguchi H, Suetsugu S, Takenawa T (2000) IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling. Nature 408:732–735.PubMedCrossRefGoogle Scholar
  90. Minard ME, Herynk MH, Collard JG, Gallick GE (2005) The guanine nucleotide exchange factor Tiam1 increases colon carcinoma growth at metastatic sites in an orthotopic nude mouse model. Oncogene 24:2568–2573.PubMedCrossRefGoogle Scholar
  91. Mitin N, Rossman KL, Der CJ (2005) Signaling interplay in Ras superfamily function. Curr Biol 15:R563–574.PubMedCrossRefGoogle Scholar
  92. Moon SY and Zheng Y (2003) Rho GTPase-activating proteins in cell regulation. Trends Cell Biol 13:13–22.PubMedCrossRefGoogle Scholar
  93. Murata T, Arii S, Nakamura T, Mori A, Kaido T, Furuyama H, Furumoto K, Nakao T, Isobe N, Imamura M (2001) Inhibitory effect of Y-27632, a ROCK inhibitor, on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells. J Hepatol 35:474–481.PubMedCrossRefGoogle Scholar
  94. Nakano K, Takaishi K, Kodama A, Mammoto A, Shiozaki H, Monden M, Takai Y (1999) Distinct actions and cooperative roles of ROCK and mDia in Rho small G protein-induced reorganization of the actin cytoskeleton in Madin-Darby canine kidney cells. Mol Biol Cell 10:2481–2491.PubMedGoogle Scholar
  95. Nobes CD and Hall A (1995) Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81:53–62.PubMedCrossRefGoogle Scholar
  96. Nobes CD, Hawkins P, Stephens L, Hall A (1995) Activation of the small GTP-binding proteins rho and rac by growth factor receptors. J Cell Sci 108 (Pt 1):225–233.PubMedGoogle Scholar
  97. Olson MF and Sahai E (2008)The actin cytoskeleton in cancer cell motility. Clin Exp Metastasis 26:273–287.Google Scholar
  98. Orimo A and Weinberg RA (2006) Stromal fibroblasts in cancer: A novel tumor-promoting cell type. Cell Cycle 5:1597–1601.PubMedCrossRefGoogle Scholar
  99. Orimo A and Weinberg RA (2007) Heterogeneity of stromal fibroblasts in tumors. Cancer Biol Ther 6:618–619.PubMedGoogle Scholar
  100. Palecek SP, Huttenlocher A, Horwitz AF, Lauffenburger DA (1998) Physical and biochemical regulation of integrin release during rear detachment of migrating cells. J Cell Sci 111 (Pt 7):929–940.PubMedGoogle Scholar
  101. Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, Kuppers R, Dalla-Favera R (2001) Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412:341–346.PubMedCrossRefGoogle Scholar
  102. Paszek MJ and Weaver VM (2004) The tension mounts: Mechanics meets morphogenesis and malignancy. J Mammary Gland Biol Neoplasia 9:325–342.PubMedCrossRefGoogle Scholar
  103. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, Reinhart-King CA, Margulies SS, Dembo M, Boettiger D, Hammer DA, Weaver VM (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254.PubMedCrossRefGoogle Scholar
  104. Pille JY, Denoyelle C, Varet J, Bertrand JR, Soria J, Opolon P, Lu H, Pritchard LL, Vannier JP, Malvy C, Soria C, Li H (2005) Anti-RhoA and anti-RhoC siRNAs inhibit the proliferation and invasiveness of MDA-MB-231 breast cancer cells in vitro and in vivo. Mol Ther 11:267–274.PubMedCrossRefGoogle Scholar
  105. Pinner S, Sahai E (2008) PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE. Nat Cell Biol 10:127–137.PubMedCrossRefGoogle Scholar
  106. Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78.PubMedCrossRefGoogle Scholar
  107. 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 (2000) 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.PubMedCrossRefGoogle Scholar
  108. Price LS and Collard JG (2001) Regulation of the cytoskeleton by Rho-family GTPases: Implications for tumour cell invasion. Semin Cancer Biol 11:167–173.PubMedCrossRefGoogle Scholar
  109. Price LS, Leng J, Schwartz MA, Bokoch GM (1998) Activation of Rac and Cdc42 by integrins mediates cell spreading. Mol Biol Cell 9:1863–1871.PubMedGoogle Scholar
  110. Provenzano PP, Eliceiri KW, Campbell JM, Inman DR, White JG, Keely PJ (2006) Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med 4:38.PubMedCrossRefGoogle Scholar
  111. Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, White JG, Keely PJ (2008) Collagen density promotes mammary tumor initiation and progression. BMC Med 6:11.PubMedCrossRefGoogle Scholar
  112. Quinlan MP (1999) Rac regulates the stability of the adherens junction and its components, thus affecting epithelial cell differentiation and transformation. Oncogene 18:6434–6442.PubMedCrossRefGoogle Scholar
  113. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z, Bissell MJ (2005) Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436:123–127.PubMedCrossRefGoogle Scholar
  114. Reuther GW, Lambert QT, Booden MA, Wennerberg K, Becknell B, Marcucci G, Sondek J, Caligiuri MA, Der CJ (2001) Leukemia-associated Rho guanine nucleotide exchange factor, a Dbl family protein found mutated in leukemia, causes transformation by activation of RhoA. J Biol Chem 276:27145–27151.PubMedCrossRefGoogle Scholar
  115. Ridley A (2000) Rho GTPases. Integrating integrin signaling. J Cell Biol 150:F107–109.PubMedCrossRefGoogle Scholar
  116. Ridley AJ (2001) Rho GTPases and cell migration. J Cell Sci 114:2713–2722.PubMedGoogle Scholar
  117. Ridley AJ (2004) Rho proteins and cancer. Breast Cancer Res Treat 84:13–19.PubMedCrossRefGoogle Scholar
  118. Ridley AJ and Hall A (1992) The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70:389–399.PubMedCrossRefGoogle Scholar
  119. Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70:401–410.PubMedCrossRefGoogle Scholar
  120. Riento K and Ridley AJ (2003) Rocks: Multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol 4:446–456.PubMedCrossRefGoogle Scholar
  121. Rohatgi R, Ma L, Miki H, Lopez M, Kirchhausen T, Takenawa T, Kirschner MW (1999) The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. Cell 97:221–231.PubMedCrossRefGoogle Scholar
  122. Rossman KL, Der CJ, Sondek J (2005) GEF means go: Turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 6:167–180.PubMedCrossRefGoogle Scholar
  123. Rottner K, Hall A, Small JV (1999) Interplay between Rac and Rho in the control of substrate contact dynamics. Curr Biol 9:640–648.PubMedCrossRefGoogle Scholar
  124. Sahai E, Marshall CJ (2002) ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nat Cell Biol 4:408–415.PubMedCrossRefGoogle Scholar
  125. Sander EE, ten Klooster JP, van Delft S, van der Kammen RA, Collard JG (1999) Rac downregulates Rho activity: Reciprocal balance between both GTPases determines cellular morphology and migratory behavior. J Cell Biol 147:1009–1022.PubMedCrossRefGoogle Scholar
  126. Sander EE, van Delft S, ten Klooster JP, Reid T, van der Kammen RA, Michiels F, Collard JG (1998) Matrix-dependent Tiam1/Rac signaling in epithelial cells promotes either cell-cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase. J Cell Biol 143:1385–1398.PubMedCrossRefGoogle Scholar
  127. Sanders LC, Matsumura F, Bokoch GM, de Lanerolle P (1999) Inhibition of myosin light chain kinase by p21-activated kinase. Science 283:2083–2085.PubMedCrossRefGoogle Scholar
  128. Saras J, Wollberg P, Aspenstrom P (2004) Wrch1 is a GTPase-deficient Cdc42-like protein with unusual binding characteristics and cellular effects. Exp Cell Res 299:356–369.PubMedCrossRefGoogle Scholar
  129. Schmidt A and Hall A (2002) Guanine nucleotide exchange factors for Rho GTPases: Turning on the switch. Genes Dev 16:1587–1609.PubMedCrossRefGoogle Scholar
  130. Schmitz AA, Govek EE, Bottner B, Van Aelst L (2000) Rho GTPases: Signaling, migration, and invasion. Exp Cell Res 261:1–12.PubMedCrossRefGoogle Scholar
  131. Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, Graeff H, Harbeck N, Schmitt M, Lengyel E (2000) Rac1 in human breast cancer: Overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19:3013–3020.PubMedCrossRefGoogle Scholar
  132. Schubbert S, Shannon K, Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7:295–308.PubMedCrossRefGoogle Scholar
  133. Sequeira L, Dubyk CW, Riesenberger TA, Cooper CR, van Golen KL (2008) Rho GTPases in PC-3 prostate cancer cell morphology, invasion and tumor cell diapedesis. Clin Exp Metastasis 25:569–579.PubMedCrossRefGoogle Scholar
  134. Shih TY, Williams DR, Weeks MO, Maryak JM, Vass WC, Scolnick EM (1978) Comparison of the genomic organization of Kirsten and Harvey sarcoma viruses. J Virol 27:45–55.PubMedGoogle Scholar
  135. Shikada Y, Yoshino I, Okamoto T, Fukuyama S, Kameyama T, Maehara Y (2003) Higher expression of RhoC is related to invasiveness in non-small cell lung carcinoma. Clin Cancer Res 9:5282–5286.PubMedGoogle Scholar
  136. Shutes A, Berzat AC, Cox AD, Der CJ (2004) Atypical mechanism of regulation of the Wrch-1 Rho family small GTPase. Curr Biol 14:2052–2056.PubMedCrossRefGoogle Scholar
  137. Small JV, Stradal T, Vignal E, Rottner K (2002) The lamellipodium: Where motility begins. Trends Cell Biol 12:112–120.PubMedCrossRefGoogle Scholar
  138. Somlyo AV, Bradshaw D, Ramos S, Murphy C, Myers CE, Somlyo AP (2000) Rho-kinase inhibitor retards migration and in vivo dissemination of human prostate cancer cells. Biochem Biophys Res Commun 269:652–659.PubMedCrossRefGoogle Scholar
  139. Suwa H, Ohshio G, Imamura T, Watanabe G, Arii S, Imamura M, Narumiya S, Hiai H, Fukumoto M (1998) Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas. Br J Cancer 77:147–152.PubMedCrossRefGoogle Scholar
  140. Takai Y, Sasaki T, Matozaki T (2001) Small GTP-binding proteins. Physiol Rev 81:153–208.PubMedGoogle Scholar
  141. Takaishi K, Sasaki T, Kato M, Yamochi W, Kuroda S, Nakamura T, Takeichi M, Takai Y (1994) Involvement of Rho p21 small GTP-binding protein and its regulator in the HGF-induced cell motility. Oncogene 9:273–279.PubMedGoogle Scholar
  142. Totsukawa G, Yamakita Y, Yamashiro S, Hartshorne DJ, Sasaki Y, Matsumura F (2000) Distinct roles of ROCK (Rho-kinase) and MLCK in spatial regulation of MLC phosphorylation for assembly of stress fibers and focal adhesions in 3T3 fibroblasts. J Cell Biol 150:797–806.PubMedCrossRefGoogle Scholar
  143. Vadlamudi RK, Adam L, Wang RA, Mandal M, Nguyen D, Sahin A, Chernoff J, Hung MC, Kumar R (2000) Regulatable expression of p21-activated kinase-1 promotes anchorage-independent growth and abnormal organization of mitotic spindles in human epithelial breast cancer cells. J Biol Chem 275:36238–36244.PubMedCrossRefGoogle Scholar
  144. Valencia A, Chardin P, Wittinghofer A, Sander C (1991) The ras protein family: Evolutionary tree and role of conserved amino acids. Biochemistry 30:4637–4648.PubMedCrossRefGoogle Scholar
  145. van Golen KL, Bao L, DiVito MM, Wu Z, Prendergast GC, Merajver SD (2002) Reversion of RhoC GTPase-induced inflammatory breast cancer phenotype by treatment with a farnesyl transferase inhibitor. Mol Cancer Ther 1:575–583.PubMedGoogle Scholar
  146. Vetter IR and Wittinghofer A (2001) The guanine nucleotide-binding switch in three dimensions. Science 294:1299–1304.PubMedCrossRefGoogle Scholar
  147. Watanabe N, Madaule P, Reid T, Ishizaki T, Watanabe G, Kakizuka A, Saito Y, Nakao K, Jockusch BM, Narumiya S (1997) p140mDia, a mammalian homolog of Drosophila diaphanous, is a target protein for Rho small GTPase and is a ligand for profilin. Embo J 16:3044–3056.PubMedCrossRefGoogle Scholar
  148. Weinberg RA (2008) Coevolution in the tumor microenvironment. Nat Genet 40:494–495.PubMedCrossRefGoogle Scholar
  149. Wennerberg K and Der CJ (2004) Rho-family GTPases: It’s not only Rac and Rho (and I like it). J Cell Sci 117:1301–1312.PubMedCrossRefGoogle Scholar
  150. Wennerberg K, Rossman KL, Der CJ (2005) The Ras superfamily at a glance. J Cell Sci 118:843–846.PubMedCrossRefGoogle Scholar
  151. Wildenberg GA, Dohn MR, Carnahan RH, Davis MA, Lobdell NA, Settleman J, Reynolds AB (2006) p120-catenin and p190RhoGAP regulate cell-cell adhesion by coordinating antagonism between Rac and Rho. Cell 127:1027–1039.PubMedCrossRefGoogle Scholar
  152. Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, Deryugina EI, Strongin AY, Brocker EB, Friedl P (2003) Compensation mechanism in tumor cell migration: Mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J Cell Biol 160:267–277.PubMedCrossRefGoogle Scholar
  153. Wong CM, Lee JM, Ching YP, Jin DY, Ng IO (2003) Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. Cancer Res 63:7646–7651.PubMedGoogle Scholar
  154. Wozniak MA, Desai R, Solski PA, Der CJ, Keely PJ (2003) ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix. J Cell Biol 163:583–595.PubMedCrossRefGoogle Scholar
  155. Wozniak MA and Keely PJ (2005) Use of three-dimensional collagen gels to study mechanotransduction in T47D breast epithelial cells. Biol Proced Online 7:144–161.PubMedCrossRefGoogle Scholar
  156. Wu M, Wu ZF, Merajver SD (2007) Rho proteins and cell-matrix interactions in cancer. Cells Tissues Organs 185:100–103.PubMedCrossRefGoogle Scholar
  157. Yap AS, Brieher WM, Gumbiner BM (1997) Molecular and functional analysis of cadherin-based adherens junctions. Annu Rev Cell Dev Biol 13:119–146.PubMedCrossRefGoogle Scholar
  158. Yuan BZ, Durkin ME, Popescu NC (2003a) Promoter hypermethylation of DLC-1, a candidate tumor suppressor gene, in several common human cancers. Cancer Genet Cytogenet 140:113–117.PubMedCrossRefGoogle Scholar
  159. Yuan BZ, Jefferson AM, Baldwin KT, Thorgeirsson SS, Popescu NC, Reynolds SH (2004) DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas. Oncogene 23:1405–1411.PubMedCrossRefGoogle Scholar
  160. Yuan BZ, Zhou X, Durkin ME, Zimonjic DB, Gumundsdottir K, Eyfjord JE, Thorgeirsson SS, Popescu NC (2003b) DLC-1 gene inhibits human breast cancer cell growth and in vivo tumorigenicity. Oncogene 22:445–450.PubMedCrossRefGoogle Scholar
  161. Zhang Y and Zhang B (2006) D4-GDI, a Rho GTPase regulator, promotes breast cancer cell invasiveness. Cancer Res 66:5592–5598.PubMedCrossRefGoogle Scholar
  162. Zhao ZS, Manser E, Loo TH, Lim L (2000) Coupling of PAK-interacting exchange factor PIX to GIT1 promotes focal complex disassembly. Mol Cell Biol 20:6354–6363.PubMedCrossRefGoogle Scholar
  163. Zhong C, Kinch MS, Burridge K (1997) Rho-stimulated contractility contributes to the fibroblastic phenotype of Ras-transformed epithelial cells. Mol Biol Cell 8:2329–2344.PubMedGoogle Scholar
  164. Zondag GC, Evers EE, ten Klooster JP, Janssen L, van der Kammen RA, Collard JG (2000) Oncogenic Ras downregulates Rac activity, which leads to increased Rho activity and epithelial-mesenchymal transition. J Cell Biol 149:775–782.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Donita C. Brady
    • 1
  • Jamie K. Alan
    • 1
  • Adrienne D. Cox
    • 2
  1. 1.Department of PharmacologyUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.Departments of Radiation Oncology and Pharmacology,Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillUSA

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