Accessible Unlicensed Requires Authentication Published by De Gruyter July 5, 2005

Oncogenic Ras in tumour progression and metastasis

Klaudia Giehl
From the journal

Abstract

The ras genes give rise to a family of related GTP-binding proteins that exhibit potent transforming potential. Mutational activation of Ras proteins promotes oncogenesis by disturbing a multitude of cellular processes, such as gene expression, cell cycle progression and cell proliferation, as well as cell survival, and cell migration. Ras signalling pathways are well known for their involvement in tumour initiation, but less is known about their contribution to invasion and metastasis. This review summarises the role and mechanisms of Ras signalling, especially the role of the Ras effector cascade Raf/MEK/ERK, as well as the phosphatidylinositol 3-kinase/Akt pathway in Ras-mediated transformation and tumour progression. In addition, it discusses the impact of Rho GTPases on Ras-mediated transformation and metastasis.

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References

Adjei, A.A. (2001). Blocking oncogenic Ras signaling for cancer therapy. J. Natl. Cancer Inst.93, 1062–1074.Search in Google Scholar

Aguirre, A.J., Bardeesy, N., Sinha, M., Lopez, L., Tuveson, D.A., Horner, J., Redston, M.S., and DePinho, R.A. (2003). Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev.17, 3112–3126.Search in Google Scholar

Ahmed, N., Niu, J., Dorahy, D.J., Gu, X., Andrews, S., Meldrum, C.J., Scott, R.J., Baker, M.S., Macreadie, I.G., and Agrez, M.V. (2002). Direct integrin αvβ6-ERK binding: implications for tumour growth. Oncogene21, 1370–1380.Search in Google Scholar

Alberts, S.R., Schroeder, M., Erlichman, C., Steen, P.D., Foster, N.R., Moore D.F. Jr., Rowland, K.M. Jr., Nair, S., Tschetter, L.K., and Fitch, T.R. (2004). Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial. J. Clin. Oncol.22, 4944–4950.Search in Google Scholar

Almoguera, C., Shibata, D., Forrester, K., Martin, J., Arnheim, N., and Perucho, M. (1988). Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell53, 549–554.Search in Google Scholar

Aoki, K., Yoshida, T., Sugimura, T., and Terada, M. (1995). Liposome-mediated in vivo gene transfer of antisense K-ras construct inhibits pancreatic tumor dissemination in the murine peritoneal cavity. Cancer Res.55, 3810–3816.Search in Google Scholar

Aoki, K., Yoshida, T., Matsumoto, N., Ide, H., Sugimura, T., and Terada, M. (1997). Suppression of Ki-ras p21 levels leading to growth inhibition of pancreatic cancer cell lines with Ki-ras mutation but not those without Ki-ras mutation. Mol. Carcinog.20, 251–258.Search in Google Scholar

Apolloni, A., Prior, I.A., Lindsay, M., Parton, R.G., and Hancock, J.F. (2000). H-Ras but not K-Ras traffics to the plasma membrane through the exocytic pathway. Mol. Cell. Biol.20, 2475–2487.Search in Google Scholar

Barbacid, M. (1987). ras genes. Annu. Rev. Biochem.56, 779–827.Search in Google Scholar

Bar-Sagi, D. and Hall, A. (2000). Ras and Rho GTPases: a family reunion. Cell103, 227–238.Search in Google Scholar

Bergo, M.O., Ambroziak, P., Gregory, C., George, A., Otto, J.C., Kim, E., Nagase, H., Casey, P.J., Balmain, A., and Young, S.G. (2002). Absence of the CAAX endoprotease Rce1: effects on cell growth and transformation. Mol. Cell. Biol.22, 171–181.Search in Google Scholar

Bergo, M.O., Gavino, B.J., Hong, C., Beigneux, A.P., McMahon, M., Casey, P.J., and Young, S.G. (2004). Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J. Clin. Invest.113, 539–550.Search in Google Scholar

Berven, L.A., Willard, F.S., and Crouch, M.F. (2004). Role of the p70(S6K) pathway in regulating the actin cytoskeleton and cell migration. Exp. Cell Res.296, 183–195.Search in Google Scholar

Bhowmick, N.A., Ghiassi, M., Bakin, A., Aakre, M., Lundquist, C.A., Engel, M.E., Arteaga, C.L., and Moses, H.L. (2001). Transforming growth factor-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol. Biol. Cell12, 27–36.Search in Google Scholar

Bian, D., Su, S., Mahanivong, C., Cheng, R.K., Han, Q., Pan, Z.K., Sun, P., and Huang, S. (2004). Lysophosphatidic acid stimulates ovarian cancer cell migration via a Ras-MEK kinase 1 pathway. Cancer Res.64, 4209–4217.Search in Google Scholar

Bishop, A.L. and Hall, A. (2000). Rho GTPases and their effector proteins. Biochem. J.348, 241–255.Search in Google Scholar

Bos, J.L. (1989). ras oncogenes in human cancer: a review. Cancer Res.49, 4682–4689.Search in Google Scholar

Bos, J.L., Fearon, E.R., Hamilton, S.R., Verlaan-de Vries, M., van Boom, J.H., van der Eb, A.J., and Vogelstein, B. (1987). Prevalence of ras gene mutations in human colorectal cancers. Nature327, 293–297.Search in Google Scholar

Braun, B.S., Tuveson, D.A., Kong, N., Le, D.T., Kogan, S.C., Rozmus, J., Le Beau, M.M., Jacks, T.E., and Shannon, K.M. (2004). Somatic activation of oncogenic K-ras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc. Natl. Acad. Sci. USA101, 597–602.Search in Google Scholar

Brazil, D.P. and Hemmings, B.A. (2001). Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem. Sci.26, 657–664.Search in Google Scholar

Brazil, D.P., Park, J., and Hemmings, B.A. (2002). PKB binding proteins. Getting in on the Akt. Cell111, 293–303.Search in Google Scholar

Brummelkamp, T.R., Bernards, R., and Agami, R. (2002). Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell2, 243–247.Search in Google Scholar

Brunet, A., Bonni, A., Zigmond, M.J., Lin, M.Z., Juo, P., Hu, L.S., Anderson, M.J., Arden, K.C., Blenis, J., and Greenberg, M.E. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell96, 857–868.Search in Google Scholar

Brunton, V.G., Fincham, V.J., McLean, G.W., Winder, S.J., Paraskeva, C., Marshall, J.F., and Frame, M.C. (2001). The protrusive phase and full development of integrin-dependent adhesions in colon epithelial cells require FAK- and ERK-mediated actin spike formation: deregulation in cancer cells. Neoplasia3, 215–226.Search in Google Scholar

Buard, A., Zipfel, P.A., Frey, R.S., and Mulder, K.M. (1996). Maintenance of growth factor signaling through Ras in human colon carcinoma cells containing K-ras mutations. Int. J. Cancer67, 539–546.Search in Google Scholar

Campbell, P.M. and Der, C.J. (2004). Oncogenic Ras and its role in tumor cell invasion and metastasis. Semin. Cancer Biol.14, 105–114.Search in Google Scholar

Camps, M., Nichols, A., and Arkinstall, S. (2000). Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J.14, 6–16.Search in Google Scholar

Cantley, L.C. (2002). The phosphoinositide 3-kinase pathway. Science296, 1655–1657.Search in Google Scholar

Carbone, A., Gusella, G.L., Radzioch, D., and Varesio, L. (1991). Human Harvey-ras is biochemically different from Kirsten- or N-ras. Oncogene6, 731–737.Search in Google Scholar

Cardone, M.H., Roy, N., Stennicke, H.R., Salvesen, G.S., Franke, T.F., Stanbridge, E., Frisch, S., and Reed, J.C. (1998). Regulation of cell death protease caspase-9 by phosphorylation. Science282, 1318–1321.Search in Google Scholar

Cherfils, J. and Chardin, P. (1999). GEFs: structural basis for their activation of small GTP-binding proteins. Trends Biochem. Sci.24, 306–311.Search in Google Scholar

Chin, L., Tam, A., Pomerantz, J., Wong, M., Holash, J., Bardeesy, N., Shen, Q., O'Hagan, R., Pantginis, J., Zhou, H., et al. (1999). Essential role for oncogenic Ras in tumour maintenance. Nature400, 468–472.Search in Google Scholar

Chiu, V.K., Bivona, T., Hach, A., Sajous, J.B., Silletti, J., Wiener, H., Johnson, R.L., Cox, A.D., and Philips, M.R. (2002). Ras signalling on the endoplasmic reticulum and the Golgi. Nat. Cell Biol.4, 343–350.Search in Google Scholar

Chong, H., Vikis, H.G., and Guan, K.L. (2003). Mechanisms of regulating the Raf kinase family. Cell Signal.15, 463–469.Search in Google Scholar

Clerk, A., Pham, F.H., Fuller, S.J., Sahai, E., Aktories, K., Marais, R., Marshall, C., and Sugden, P.H. (2001). Regulation of mitogen-activated protein kinases in cardiac myocytes through the small G protein Rac1. Mol. Cell. Biol.21, 1173–1184.Search in Google Scholar

Coles, L.C. and Shaw, P.E. (2002). PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway. Oncogene21, 2236–2244.Search in Google Scholar

Datta, S.R., Brunet, A., and Greenberg, M.E. (1999). Cellular survival: a play in three Akts. Genes Dev.13, 2905–2927.Search in Google Scholar

Davies, H., Bignell, G.R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M.J., Bottomley, W., et al. (2002). Mutations of the BRAF gene in human cancer. Nature417, 949–954.Search in Google Scholar

Dhillon, A.S., Meikle, S., Yazici, Z., Eulitz, M., and Kolch, W. (2002). Regulation of Raf-1 activation and signalling by dephosphorylation. EMBO J.21, 64–71.Search in Google Scholar

Diaz-Meco, M.T., Lozano, J., Municio, M.M., Berra, E., Frutos, S., Sanz, L., and Moscat, J. (1994). Evidence for the in vitro and in vivo interaction of Ras with protein kinase C zeta. J. Biol. Chem.269, 31706–31710.Search in Google Scholar

Donovan, S., Shannon, K.M., and Bollag, G. (2002). GTPase activating proteins: critical regulators of intracellular signaling. Biochim. Biophys. Acta1602, 23–45.Search in Google Scholar

Downward, J. (1997). Role of phosphoinositide-3-OH kinase in Ras signaling. Adv. Second Messenger Phosphoprotein Res.31, 1–10.Search in Google Scholar

Downward, J. (1998). Lipid-regulated kinases: some common themes at last. Science279, 673–674.Search in Google Scholar

Downward, J. (2003). Role of receptor tyrosine kinases in G-protein-coupled receptor regulation of Ras: transactivation or parallel pathways?Biochem. J.376, 9–10.Search in Google Scholar

Downward, J. (2004). PI 3-kinase, Akt and cell survival. Semin. Cell Dev. Biol.15, 177–182.Search in Google Scholar

Duursma, A.M. and Agami, R. (2003). Ras interference as cancer therapy. Semin. Cancer Biol.13, 267–273.Search in Google Scholar

Ehrhardt, A., Ehrhardt, G.R., Guo, X., and Schrader, J.W. (2002). Ras and relatives – job sharing and networking keep an old family together. Exp. Hematol.30, 1089–1106.Search in Google Scholar

Elad-Sfadia, G., Haklai, R., Ballan, E., Gabius, H.J., and Kloog, Y. (2002). Galectin-1 augments Ras activation and diverts Ras signals to Raf-1 at the expense of phosphoinositide 3-kinase. J. Biol. Chem.277, 37169–37175.Search in Google Scholar

Elad-Sfadia, G., Haklai, R., Balan, E., and Kloog, Y. (2004). Galectin-3 augments K-Ras activation and triggers a Ras signal that attenuates ERK but not phosphoinositide 3-kinase activity. J. Biol. Chem.279, 34922–34930.Search in Google Scholar

Elbashir, S.M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K., and Tuschl, T. (2001). Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature411, 494–498.Search in Google Scholar

Ellis, C.A. and Clark, G. (2000). The importance of being K-Ras. Cell Signal. 12, 425–434.Search in Google Scholar

Esteban, L.M., Vicario-Abejon, C., Fernandez-Salguero, P., Fernandez-Medarde, A., Swaminathan, N., Yienger, K., Lopez, E., Malumbres, M., McKay, R., Ward, J.M., et al. (2001). Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development. Mol. Cell. Biol.21, 1444–1452.Search in Google Scholar

Etienne-Manneville, S. and Hall, A. (2002). Rho GTPases in cell biology. Nature420, 629–635.Search in Google Scholar

Fan, W.T., Koch, C.A., de Hoog, C.L., Fam, N.P., and Moran, M.F. (1998). The exchange factor Ras-GRF2 activates Ras-dependent and Rac-dependent mitogen-activated protein kinase pathways. Curr. Biol.8, 935–938.Search in Google Scholar

Feig, L.A. (1999). Tools of the trade: use of dominant-inhibitory mutants of Ras-family GTPases. Nat. Cell Biol.1, E25–E27.Search in Google Scholar

Fensterer, H., Giehl, K., Buchholz, M., Ellenrieder, V., Buck, A., Kestler, H.A., Adler, G., Gierschik, P., and Gress, T.M. (2004). Expression profiling of the influence of RAS mutants on the TGFB1-induced phenotype of the pancreatic cancer cell line PANC-1. Genes Chromosomes Cancer39, 224–235.Search in Google Scholar

Fleming, I.N., Gray, A., and Downes, C.P. (2000). Regulation of the Rac1-specific exchange factor Tiam1 involves both phosphoinositide 3-kinase-dependent and -independent components. Biochem. J.351, 173–182.Search in Google Scholar

Franke, T.F., Hornik, C.P., Segev, L., Shostak, G.A., and Sugimoto, C. (2003). PI3K/Akt and apoptosis: size matters. Oncogene22, 8983–8998.Search in Google Scholar

Frost, J.A., Steen, H., Shapiro, P., Lewis, T., Ahn, N., Shaw, P.E., and Cobb, M.H. (1997). Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins. EMBO J.16, 6426–6438.Search in Google Scholar

Gallagher, E.D., Gutowski, S., Sternweis, P.C., and Cobb, M.H. (2004). RhoA binds to the amino-terminus of MEKK1 and regulates its kinase activity. J. Biol. Chem.279, 1872–1877.Search in Google Scholar

Giehl, K., Seidel, B., Gierschik, P., Adler, G., and Menke, A. (2000a). TGFβ1 represses proliferation of pancreatic carcinoma cells which correlates with Smad4-independent inhibition of ERK activation. Oncogene19, 4531–4541.Search in Google Scholar

Giehl, K., Skripczynski, B., Mansard, A., Menke, A., and Gierschik, P. (2000b). Growth factor-dependent activation of the Ras-Raf-MEK-MAPK pathway in the human pancreatic carcinoma cell line PANC-1 carrying activated K-ras: implications for cell proliferation and cell migration. Oncogene19, 2930–2942.Search in Google Scholar

Gotzmann, J., Mikula, M., Eger, A., Schulte-Hermann, R., Foisner, R., Beug, H., and Mikulits, W. (2004). Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis. Mutat. Res.566, 9–20.Search in Google Scholar

Grille, S.J., Bellacosa, A., Upson, J., Klein-Szanto, A.J., van Roy, F., Lee-Kwon, W., Donowitz, M., Tsichlis, P.N., and Larue, L. (2003). The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res.63, 2172–2178.Search in Google Scholar

Grunert, S., Jechlinger, M., and Beug, H. (2003). Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat. Rev. Mol. Cell Biol.4, 657–665.Search in Google Scholar

Gupta, S., Plattner, R., Der, C.J., and Stanbridge, E.J. (2000). Dissection of Ras-dependent signaling pathways controlling aggressive tumor growth of human fibrosarcoma cells: evidence for a potential novel pathway. Mol. Cell. Biol.20, 9294–9306.Search in Google Scholar

Hahn, W.C. and Weinberg, R.A. (2002). Modelling the molecular circuitry of cancer. Nat. Rev. Cancer2, 331–341.Search in Google Scholar

Haklai, R., Weisz, M.G., Elad, G., Paz, A., Marciano, D., Egozi, Y., Ben Baruch, G., and Kloog, Y. (1998). Dislodgement and accelerated degradation of Ras. Biochemistry37, 1306–1314.Search in Google Scholar

Hamad, N.M., Elconin, J.H., Karnoub, A.E., Bai, W., Rich, J.N., Abraham, R.T., Der, C.J., and Counter, C.M. (2002). Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev.16, 2045–2057.Search in Google Scholar

Hamilton, M. and Wolfman, A. (1998). Ha-ras and N-ras regulate MAPK activity by distinct mechanisms in vivo. Oncogene16, 1417–1428.Search in Google Scholar

Han, L. and Colicelli, J. (1995). A human protein selected for interference with Ras function interacts directly with Ras and competes with Raf1. Mol. Cell. Biol.15, 1318–1323.Search in Google Scholar

Hancock, J.F. (2003). Ras proteins: different signals from different locations. Nat. Rev. Mol. Cell Biol.4, 373–384.Search in Google Scholar

Herrera, R. and Sebolt-Leopold, J.S. (2002). Unraveling the complexities of the Raf/MAP kinase pathway for pharmacological intervention. Trends Mol. Med.8, S27–S31.Search in Google Scholar

Herrmann, C. (2003). Ras-effector interactions: after one decade. Curr. Opin. Struct. Biol.13, 122–129.Search in Google Scholar

Howe, L.R., Leevers, S.J., Gomez, N., Nakielny, S., Cohen, P., and Marshall, C.J. (1992). Activation of the MAP kinase pathway by the protein kinase raf. Cell71, 335–342.Search in Google Scholar

Hruban, R.H., Wilentz, R.E., and Kern, S.E. (2000). Genetic progression in the pancreatic ducts. Am. J. Pathol.156, 1821–1825.Search in Google Scholar

Hu, K.Q. and Settleman, J. (1997). Tandem SH2 binding sites mediate the RasGAP-RhoGAP interaction: a conformational mechanism for SH3 domain regulation. EMBO J.16, 473–483.Search in Google Scholar

Huang, C., Jacobson, K., and Schaller, M.D. (2004). MAP kinases and cell migration. J. Cell Sci.117, 4619–4628.Search in Google Scholar

Innocenti, M., Tenca, P., Frittoli, E., Faretta, M., Tocchetti, A., Di Fiore, P.P., and Scita, G. (2002). Mechanisms through which Sos-1 coordinates the activation of Ras and Rac. J. Cell Biol.156, 125–136.Search in Google Scholar

Janda, E., Lehmann, K., Killisch, I., Jechlinger, M., Herzig, M., Downward, J., Beug, H., and Grunert, S. (2002). Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J. Cell Biol.156, 299–313.Search in Google Scholar

Jiang, K., Sun, J., Cheng, J., Djeu, J.Y., Wei, S., and Sebti, S. (2004). Akt mediates Ras downregulation of RhoB, a suppressor of transformation, invasion, and metastasis. Mol. Cell Biol.24, 5565–5576.Search in Google Scholar

Jiang, X. and Sorkin, A. (2002). Coordinated traffic of Grb2 and Ras during epidermal growth factor receptor endocytosis visualized in living cells. Mol. Biol. Cell13, 1522–1535.Search in Google Scholar

Johnson, G.L. and Lapadat, R. (2002). Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science298, 1911–1912.Search in Google Scholar

Johnson, L., Mercer, K., Greenbaum, D., Bronson, R.T., Crowley, D., Tuveson, D.A., and Jacks, T. (2001). Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature410, 1111–1116.Search in Google Scholar

Kelley, G.G., Reks, S.E., Ondrako, J.M., and Smrcka, A.V. (2001). Phospholipase C(epsilon): a novel Ras effector. EMBO J.20, 743–754.Search in Google Scholar

Khosravi-Far, R., White, M.A., Westwick, J.K., Solski, P.A., Chrzanowska Wodnicka, M., Van Aelst, L., Wigler, M.H., and Der, C.J. (1996). Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol. Cell. Biol.16, 3923–3933.Search in Google Scholar

Khosravi-Far, R., Campbell, S., Rossman, K.L., and Der, C.J. (1998). Increasing complexity of Ras signal transduction: involvement of Rho family proteins. Adv. Cancer Res.72, 57–107.Search in Google Scholar

Kim, D., Kim, S., Koh, H., Yoon, S.O., Chung, A.S., Cho, K.S., and Chung, J. (2001). Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J.15, 1953–1962.Search in Google Scholar

Kim, K., Lindstrom, M.J., and Gould, M.N. (2002). Regions of H- and K-Ras that provide organ specificity/potency in mammary cancer induction. Cancer Res.62, 1241–1245.Search in Google Scholar

King, A.J., Sun, H., Diaz, B., Barnard, D., Miao, W., Bagrodia, S., and Marshall, M.S. (1998). The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338. Nature396, 180–183.Search in Google Scholar

Kjoller, L. and Hall, A. (1999). Signaling to Rho GTPases. Exp. Cell Res.253, 166–179.Search in Google Scholar

Klemke, R.L., Cai, S., Giannini, A.L., Gallagher, P.J., de, L.P., and Cheresh, D.A. (1997). Regulation of cell motility by mitogen-activated protein kinase. J. Cell Biol.137, 481–492.Search in Google Scholar

Kloog, Y. and Cox, A.D. (2000). Ras inhibitors: potential for cancer therapeutics. Mol. Med. Today6, 398–402.Search in Google Scholar

Kloog, Y. and Cox, A.D. (2004). Prenyl-binding domains: potential targets for Ras inhibitors and anti-cancer drugs. Semin. Cancer Biol.14, 253–261.Search in Google Scholar

Koera, K., Nakamura, K., Nakao, K., Miyoshi, J., Toyoshima, K., Hatta, T., Otani, H., Aiba, A., and Katsuki, M. (1997). K-ras is essential for the development of the mouse embryo. Oncogene15, 1151–1159.Search in Google Scholar

Kulkarni, S.V., Gish, G., van der, G.P., Henkemeyer, M., and Pawson, T. (2000). Role of p120 Ras-GAP in directed cell movement. J. Cell Biol.149, 457–470.Search in Google Scholar

Kuriyama, M., Harada, N., Kuroda, S., Yamamoto, T., Nakafuku, M., Iwamatsu, A., Yamamoto, D., Prasad, R., Croce, C., Canaani, E., and Kaibuchi, K. (1996). Identification of AF-6 and canoe as putative targets for Ras. J. Biol. Chem.271, 607–610.Search in Google Scholar

Lambert, J.M., Lambert, Q.T., Reuther, G.W., Malliri, A., Siderovski, D.P., Sondek, J., Collard, J.G., and Der, C.J. (2002). Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nat. Cell Biol.4, 621–625.Search in Google Scholar

Lange-Carter, C.A. and Johnson, G.L. (1994). Ras-dependent growth factor regulation of MEK kinase in PC12 cells. Science265, 1458–1461.Search in Google Scholar

Lerner, E.C., Qian, Y., Blaskovich, M.A., Fossum, R.D., Vogt, A., Sun, J., Cox, A.D., Der, C.J., Hamilton, A.D., and Sebti, S.M. (1995). Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J. Biol. Chem.270, 26802–26806.Search in Google Scholar

Liao, J., Wolfman, J.C., and Wolfman, A. (2003). K-Ras regulates the steady-state expression of matrix metalloproteinase 2 in fibroblasts. J. Biol. Chem.278, 31871–37878.Search in Google Scholar

Lozano, E., Betson, M., and Braga, V.M. (2003). Tumor progression: small GTPases and loss of cell-cell adhesion. Bioessays25, 452–463.Search in Google Scholar

Luo, J., Manning, B.D., and Cantley, L.C. (2003). Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell. 4, 257–262.Search in Google Scholar

Luo, W. and Sharif, M. (1999). Stable expression of activated Ki-Ras does not constitutively activate the mitogen-activated protein kinase pathway but attenuates epidermal growth factor receptor activation in human astrocytoma cells. Int. J. Oncol.14, 53–62.Search in Google Scholar

Malliri, A., van der Kammen, R.A., Clark, K., van, d., V, Michiels, F., and Collard, J.G. (2002). Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature417, 867–871.Search in Google Scholar

Malumbres, M. and Barbacid, M. (2003). RAS oncogenes: the first 30 years. Nat. Rev. Cancer3, 459–465.Search in Google Scholar

Matallanas, D., Arozarena, I., Berciano, M.T., Aaronson, D.S., Pellicer, A., Lafarga, M., and Crespo, P. (2003). Differences on the inhibitory specificities of H-Ras, K-Ras and N-Ras (N17) dominant negative mutants are related to their membrane microlocalization. J. Biol. Chem.278, 4572–4581.Search in Google Scholar

Mazieres, J., Antonia, T., Daste, G., Muro-Cacho, C., Berchery, D., Tillement, V., Pradines, A., Sebti, S., and Favre, G. (2004). Loss of RhoB expression in human lung cancer progression. Clin. Cancer Res.10, 2742–2750.Search in Google Scholar

Meili, R., Ellsworth, C., Lee, S., Reddy, T.B., Ma, H., and Firtel, R.A. (1999). Chemoattractant-mediated transient activation and membrane localization of Akt/PKB is required for efficient chemotaxis to cAMP in Dictyostelium. EMBO J.18, 2092–2105.Search in Google Scholar

Nakada, Y., Saito, S., Ohzawa, K., Morioka, C.Y., Kita, K., Minemura, M., Takahara, T., and Watanabe, A. (2001). Antisense oligonucleotides specific to mutated K-ras genes inhibit invasiveness of human pancreatic cancer cell lines. Pancreatology1, 314–319.Search in Google Scholar

Nobes, C.D. and Hall, A. (1995). Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell81, 53–62.Search in Google Scholar

Nobes, C.D. and Hall, A. (1999). Rho GTPases control polarity, protrusion, and adhesion during cell movement. J. Cell Biol.144, 1235–1244.Search in Google Scholar

Noren, N.K., Arthur, W.T., and Burridge, K. (2003). Cadherin engagement inhibits RhoA via p190RhoGAP. J. Biol. Chem.278, 13615–13618.Search in Google Scholar

Park, B.K., Zeng, X., and Glazer, R.I. (2001). Akt1 induces extracellular matrix invasion and matrix metalloproteinase-2 activity in mouse mammary epithelial cells. Cancer Res.61, 7647–7653.Search in Google Scholar

Pawlak, G. and Helfman, D.M. (2001). Cytoskeletal changes in cell transformation and tumorigenesis. Curr. Opin. Genet. Dev.11, 41–47.Search in Google Scholar

Pawlak, G. and Helfman, D.M. (2002). Post-transcriptional down-regulation of ROCKI/Rho-kinase through an MEK-dependent pathway leads to cytoskeleton disruption in Ras-transformed fibroblasts. Mol. Biol. Cell13, 336–347.Search in Google Scholar

Prior, I.A., Harding, A., Yan, J., Sluimer, J., Parton, R.G., and Hancock, J.F. (2001). GTP-dependent segregation of H-ras from lipid rafts is required for biological activity. Nat. Cell Biol.3, 368–375.Search in Google Scholar

Prior, I.A., Muncke, C., Parton, R.G., and Hancock, J.F. (2003). Direct visualization of Ras proteins in spatially distinct cell surface microdomains. J. Cell Biol.160, 165–170.Search in Google Scholar

Qian, Y., Corum, L., Meng, Q., Blenis, J., Zheng, J.Z., Shi, X., Flynn, D.C., and Jiang, B.H. (2004). PI3K induced actin filament remodeling through Akt and p70S6K1: implication of essential role in cell migration. Am. J. Physiol. Cell Physiol.286, C153–C163.Search in Google Scholar

Quinlan, M.P. (1999). Rac regulates the stability of the adherens junction and its components, thus affecting epithelial cell differentiation and transformation. Oncogene18, 6434–6442.Search in Google Scholar

Raftopoulou, M. and Hall, A. (2004). Cell migration: Rho GTPases lead the way. Dev. Biol.265, 23–32.Search in Google Scholar

Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K.W., Vogelstein, B., and Velculescu, V.E. (2002). Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature418, 934.Search in Google Scholar

Ridley, A.J. (2001). Rho family proteins: coordinating cell responses. Trends Cell Biol.11, 471–477.Search in Google Scholar

Ridley, A.J. (2004). Rho proteins and cancer. Breast Cancer Res. Treat.84, 13–19.Search in Google Scholar

Ridley, A.J., Schwartz, M.A., Burridge, K., Firtel, R.A., Ginsberg, M.H., Borisy, G., Parsons, J.T., and Horwitz, A.R. (2003). Cell migration: integrating signals from front to back. Science302, 1704–1709.Search in Google Scholar

Rodenhuis, S., Slebos, R.J., Boot, A.J., Evers, S.G., Mooi, W.J., Wagenaar, S.S., van Bodegom, P.C., and Bos, J.L. (1988). Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res.48, 5738–5741.Search in Google Scholar

Rodriguez Viciana, P., Warne, P.H., Dhand, R., Vanhaesebroeck, B., Gout, I., Fry, M.J., Waterfield, M.D., and Downward, J. (1994). Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature370, 527–532.Search in Google Scholar

Roof, R.W., Haskell, M.D., Dukes, B.D., Sherman, N., Kinter, M., and Parsons, S.J. (1998). Phosphotyrosine (p-Tyr)-dependent and -independent mechanisms of p190 RhoGAP-p120 RasGAP interaction: Tyr 1105 of p190, a substrate for c-src, is the sole p-Tyr mediator of complex formation. Mol. Cell. Biol.18, 7052–7063.Search in Google Scholar

Ross, P.J., George, M., Cunningham, D., DiStefano, F., Andreyev, H.J., Workman, P., and Clarke, P.A. (2001). Inhibition of Kirsten-ras expression in human colorectal cancer using rationally selected Kirsten-ras antisense oligonucleotides. Mol. Cancer Ther.1, 29–41.Search in Google Scholar

Roy, S., Luetterforst, R., Harding, A., Apolloni, A., Etheridge, M., Stang, E., Rolls, B., Hancock, J.F., and Parton, R.G. (1999). Dominant-negative caveolin inhibits H-Ras function by disrupting cholesterol-rich plasma membrane domains. Nat. Cell Biol.1, 98–105.Search in Google Scholar

Roy, S., Wyse, B., and Hancock, J.F. (2002). H-Ras signaling and K-Ras signaling are differentially dependent on endocytosis. Mol. Cell. Biol.22, 5128–5140.Search in Google Scholar

Sahai, E. and Marshall, C.J. (2002). Rho-GTPases and cancer. Nat. Rev. Cancer2, 133–142.Search in Google Scholar

Sahai, E., Olson, M.F., and Marshall, C.J. (2001). Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility. EMBO J.20, 755–766.Search in Google Scholar

Sander, E.E. and Collard, J.G. (1999). Rho-like GTPases: their role in epithelial cell-cell adhesion and invasion. Eur. J. Cancer.35, 1302–1308.Search in Google Scholar

Scheffzek, K., Ahmadian, M.R., Kabsch, W., Wiesmuller, L., Lautwein, A., Schmitz, F., and Wittinghofer, A. (1997). The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science277, 333–338.Search in Google Scholar

Sebti, S.M. and Adjei, A.A. (2004). Farnesyltransferase inhibitors. Semin. Oncol.31, 28–39.Search in Google Scholar

Serrano, M., Lin, A.W., McCurrach, M.E., Beach, D., and Lowe, S.W. (1997). Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell88, 593–602.Search in Google Scholar

Shaw, L.M., Rabinovitz, I., Wang, H.H., Toker, A., and Mercurio, A.M. (1997). Activation of phosphoinositide 3-OH kinase by the α6β4 integrin promotes carcinoma invasion. Cell91, 949–960.Search in Google Scholar

Shields, J.M., Pruitt, K., McFall, A., Shaub, A., and Der, C.J. (2000). Understanding Ras: ‘it ain't over 'til it's over’. Trends Cell Biol.10, 147–154.Search in Google Scholar

Silvius, J.R. (2002). Mechanisms of ras protein targeting in mammalian cells. J. Membr. Biol.190, 83–92.Search in Google Scholar

Sinn, E., Muller, W., Pattengale, P., Tepler, I., Wallace, R., and Leder, P. (1987). Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell. 49, 465–475.Search in Google Scholar

Skinner, J., Bounacer, A., Bond, J.A., Haughton, M.F., DeMicco, C., and Wynford-Thomas, D. (2004). Opposing effects of mutant ras oncoprotein on human fibroblast and epithelial cell proliferation: implications for models of human tumorigenesis. Oncogene23, 5994–5999.Search in Google Scholar

Stacey, D.W., Feig, L.A., and Gibbs, J.B. (1991). Dominant inhibitory Ras mutants selectively inhibit the activity of either cellular or oncogenic Ras. Mol. Cell. Biol.11, 4053–4064.Search in Google Scholar

Stahle, M., Veit, C., Bachfischer, U., Schierling, K., Skripczynski, B., Hall, A., Gierschik, P., and Giehl, K. (2003). Mechanisms in LPA-induced tumor cell migration: critical role of phosphorylated ERK. J. Cell Sci.116, 3835–3846.Search in Google Scholar

Takai, Y., Sasaki, T., and Matozaki, T. (2001). Small GTP-binding proteins. Physiol. Rev.81, 153–208.Search in Google Scholar

Tang, Y., Yu, J., and Field, J. (1999). Signals from the Ras, Rac, and Rho GTPases converge on the Pak protein kinase in Rat-1 fibroblasts. Mol. Cell. Biol.19, 1881–1891.Search in Google Scholar

Tanno, S., Tanno, S., Mitsuuchi, Y., Altomare, D.A., Xiao, G.H., and Testa, J.R. (2001). AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res.61, 589–593.Search in Google Scholar

Testa, J.R. and Bellacosa, A. (2001). AKT plays a central role in tumorigenesis. Proc. Natl. Acad. Sci. USA98, 10983–10985.Search in Google Scholar

Thissen, J.A., Gross, J.M., Subramanian, K., Meyer, T., and Casey, P.J. (1997). Prenylation-dependent association of Ki-Ras with microtubules. Evidence for a role in subcellular trafficking. J. Biol. Chem.272, 30362–30370.Search in Google Scholar

Treisman, R. (1996). Regulation of transcription by MAP kinase cascades. Curr. Opin. Cell Biol.8, 205–215.Search in Google Scholar

Vanhaesebroeck, B. and Alessi, D.R. (2000). The PI3K-PDK1 connection: more than just a road to PKB. Biochem. J.346, 561–576.Search in Google Scholar

Vasko, V., Saji, M., Hardy, E., Kruhlak, M., Larin, A., Savchenko, V., Miyakawa, M., Isozaki, O., Murakami, H., Tsushima, T., et al. (2004). Akt activation and localisation correlate with tumour invasion and oncogene expression in thyroid cancer. J. Med. Genet.41, 161–170.Search in Google Scholar

Vavvas, D., Li, X., Avruch, J., and Zhang, X.F. (1998). Identification of Nore1 as a potential Ras effector. J. Biol. Chem.273, 5439–5442.Search in Google Scholar

Veit, C., Genze, F., Menke, A., Hoeffert, S., Gress, T.M., Gierschik, P., and Giehl, K. (2004). Activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase is required for glial cell line-derived neurotrophic factor-induced migration and invasion of pancreatic carcinoma cells. Cancer Res.64, 5291–5300.Search in Google Scholar

Vivanco, I. and Sawyers, C.L. (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer2, 489–501.Search in Google Scholar

Voice, J.K., Klemke, R.L., Le, A., and Jackson, J.H. (1999). Four human Ras homologs differ in their abilities to activate Raf-1, induce transformation, and stimulate cell motility. J. Biol. Chem.274, 17164–17170.Search in Google Scholar

Webb, C.P., Van, A.L., Wigler, M.H., and Woude, G.F. (1998). Signaling pathways in Ras-mediated tumorigenicity and metastasis. Proc. Natl. Acad. Sci. USA95, 8773–8778.Search in Google Scholar

Weisz, B., Giehl, K., Gana-Weisz, M., Egozi, Y., Ben Baruch, G., Marciano, D., Gierschik, P., and Kloog, Y. (1999). A new functional Ras antagonist inhibits human pancreatic tumor growth in nude mice. Oncogene18, 2579–2588.Search in Google Scholar

Wells, A. (2000). Tumor invasion: role of growth factor-induced cell motility. Adv. Cancer Res.78, 31–101.Search in Google Scholar

Wetzker, R. and Rommel, C. (2004). Phosphoinositide 3-kinases as targets for therapeutic intervention. Curr. Pharm. Des.10, 1915–1922.Search in Google Scholar

Whyte, D.B., Kirschmeier, P., Hockenberry, T.N., Nunez Oliva, I., James, L., Catino, J.J., Bishop, W.R., and Pai, J.K. (1997). K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J. Biol. Chem.272, 14459–14464.Search in Google Scholar

Wolthuis, R.M.F., Zwartkruis, F., Moen, T.C., and Bos, J.L. (1998). Ras-dependent activation of the small GTPase Ral. Curr. Biol.8, 471–474.Search in Google Scholar

Wymann, M.P., Zvelebil, M., and Laffargue, M. (2003). Phosphoinositide 3-kinase signalling – which way to target?Trends Pharmacol. Sci.24, 366–376.Search in Google Scholar

Yan, J., Roy, S., Apolloni, A., Lane, A., and Hancock, J.F. (1998). Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J. Biol. Chem.273, 24052–24056.Search in Google Scholar

Yan, Z., Chen, M., Perucho, M., and Friedman, E. (1997a). Oncogenic Ki-ras but not oncogenic Ha-ras blocks integrin β1-chain maturation in colon epithelial cells. J. Biol. Chem.272, 30928–30936.Search in Google Scholar

Yan, Z., Deng, X., Chen, M., Xu, Y., Ahram, M., Sloane, B.F., and Friedman, E. (1997b). Oncogenic c-Ki-ras but not oncogenic c-Ha-ras up-regulates CEA expression and disrupts basolateral polarity in colon epithelial cells. J. Biol. Chem.272, 27902–27907.Search in Google Scholar

Yang, G., Thompson, J.A., Fang, B., and Liu, J. (2003). Silenc-ing of H-ras gene expression by retrovirus-mediated siRNA decreases transformation efficiency and tumor growth in a model of human ovarian cancer. Oncogene22, 5694–5701.Search in Google Scholar

Yip-Schneider, M.T., Lin, A., Barnard, D., Sweeney, C.J., and Marshall, M.S. (1999). Lack of elevated MAP kinase (Erk) activity in pancreatic carcinomas despite oncogenic K-ras expression. Int. J. Oncol.15, 271–279.Search in Google Scholar

Yip-Schneider, M.T., Lin, A., and Marshall, M.S. (2001). Pancreatic tumor cells with mutant K-ras suppress ERK activity by MEK-dependent induction of MAP kinase phosphatase-2. Biochem. Biophys. Res. Commun.280, 992–997.Search in Google Scholar

Zondag, G.C., Evers, E.E., ten Klooster, J.P., Janssen, L., Der Kammen, R.A., and Collard, J.G. (2000). Oncogenic ras downregulates rac activity, which leads to increased rho activity and epithelial-mesenchymal transition. J. Cell Biol.149, 775–782.Search in Google Scholar

Published Online: 2005-07-05
Published in Print: 2005-03-01

©2004 by Walter de Gruyter Berlin New York