Oncogenic Ras in tumour progression and metastasis

References

Adjei, A.A. (2001). Blocking oncogenic Ras signaling for cancer therapy. J. Natl. Cancer Inst.93, 1062–1074.10.1093/jnci/93.14.1062Search 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, 3112–3126.10.1101/gad.1158703Search 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, 1370–1380.10.1038/sj.onc.1205286Search 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, 4944–4950.10.1200/JCO.2004.05.034Search 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, 549–554.10.1016/0092-8674(88)90571-5Search 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, 251–258.10.1002/(SICI)1098-2744(199710)20:2<251::AID-MC12>3.0.CO;2-9Search 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, 2475–2487.10.1128/MCB.20.7.2475-2487.2000Search in Google Scholar

Barbacid, M. (1987). ras genes. Annu. Rev. Biochem.56, 779–827.10.1146/annurev.bi.56.070187.004023Search in Google Scholar

Bar-Sagi, D. and Hall, A. (2000). Ras and Rho GTPases: a family reunion. Cell103, 227–238.10.1016/S0092-8674(00)00115-XSearch 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, 171–181.10.1128/MCB.22.1.171-181.2002Search 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, 539–550.10.1172/JCI200418829Search 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, 183–195.10.1016/j.yexcr.2003.12.032Search 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, 27–36.10.1091/mbc.12.1.27Search 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, 4209–4217.10.1158/0008-5472.CAN-04-0060Search in Google Scholar

Bishop, A.L. and Hall, A. (2000). Rho GTPases and their effector proteins. Biochem. J.348, 241–255.10.1042/bj3480241Search 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, 293–297.10.1038/327293a0Search 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, 597–602.10.1073/pnas.0307203101Search 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, 657–664.10.1016/S0968-0004(01)01958-2Search in Google Scholar

Brazil, D.P., Park, J., and Hemmings, B.A. (2002). PKB binding proteins. Getting in on the Akt. Cell111, 293–303.10.1016/S0092-8674(02)01083-8Search in Google Scholar

Brummelkamp, T.R., Bernards, R., and Agami, R. (2002). Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell2, 243–247.10.1016/S1535-6108(02)00122-8Search 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, 857–868.10.1016/S0092-8674(00)80595-4Search 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, 215–226.10.1038/sj.neo.7900149Search 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, 539–546.10.1002/(SICI)1097-0215(19960807)67:4<539::AID-IJC13>3.0.CO;2-2Search 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, 105–114.10.1016/j.semcancer.2003.09.015Search 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, 6–16.10.1096/fasebj.14.1.6Search in Google Scholar

Cantley, L.C. (2002). The phosphoinositide 3-kinase pathway. Science296, 1655–1657.10.1126/science.296.5573.1655Search 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, 1318–1321.10.1126/science.282.5392.1318Search in Google Scholar

Cherfils, J. and Chardin, P. (1999). GEFs: structural basis for their activation of small GTP-binding proteins. Trends Biochem. Sci.24, 306–311.10.1016/S0968-0004(99)01429-2Search 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, 468–472.10.1038/22788Search 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, 343–350.10.1038/ncb783Search in Google Scholar

Chong, H., Vikis, H.G., and Guan, K.L. (2003). Mechanisms of regulating the Raf kinase family. Cell Signal.15, 463–469.10.1016/S0898-6568(02)00139-0Search 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, 1173–1184.10.1128/MCB.21.4.1173-1184.2001Search 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, 2236–2244.10.1038/sj.onc.1205302Search in Google Scholar

Datta, S.R., Brunet, A., and Greenberg, M.E. (1999). Cellular survival: a play in three Akts. Genes Dev.13, 2905–2927.10.1101/gad.13.22.2905Search 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, 949–954.10.1038/nature00766Search 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, 64–71.10.1093/emboj/21.1.64Search 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, 31706–31710.10.1016/S0021-9258(18)31753-8Search in Google Scholar

Donovan, S., Shannon, K.M., and Bollag, G. (2002). GTPase activating proteins: critical regulators of intracellular signaling. Biochim. Biophys. Acta1602, 23–45.10.1016/S0304-419X(01)00041-5Search in Google Scholar

Downward, J. (1997). Role of phosphoinositide-3-OH kinase in Ras signaling. Adv. Second Messenger Phosphoprotein Res.31, 1–10.10.1016/S1040-7952(97)80004-3Search in Google Scholar

Downward, J. (1998). Lipid-regulated kinases: some common themes at last. Science279, 673–674.10.1126/science.279.5351.673Search in Google Scholar PubMed

Downward, J. (2003). Role of receptor tyrosine kinases in G-protein-coupled receptor regulation of Ras: transactivation or parallel pathways?Biochem. J.376, 9–10.10.1042/bj20031745Search in Google Scholar

Downward, J. (2004). PI 3-kinase, Akt and cell survival. Semin. Cell Dev. Biol.15, 177–182.10.1016/j.semcdb.2004.01.002Search in Google Scholar

Duursma, A.M. and Agami, R. (2003). Ras interference as cancer therapy. Semin. Cancer Biol.13, 267–273.10.1016/S1044-579X(03)00040-3Search 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, 1089–1106.10.1016/S0301-472X(02)00904-9Search 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, 37169–37175.10.1074/jbc.M205698200Search 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, 34922–34930.10.1074/jbc.M312697200Search 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, 494–498.10.1038/35078107Search in Google Scholar

Ellis, C.A. and Clark, G. (2000). The importance of being K-Ras. Cell Signal. 12, 425–434.10.1016/S0898-6568(00)00084-XSearch 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, 1444–1452.10.1128/MCB.21.5.1444-1452.2001Search in Google Scholar PubMed PubMed Central

Etienne-Manneville, S. and Hall, A. (2002). Rho GTPases in cell biology. Nature420, 629–635.10.1038/nature01148Search in Google Scholar PubMed

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, 935–938.10.1016/S0960-9822(07)00376-4Search 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–E27.10.1038/10018Search 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, 224–235.10.1002/gcc.20000Search 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, 173–182.10.1042/bj3510173Search 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, 8983–8998.10.1038/sj.onc.1207115Search 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, 6426–6438.10.1093/emboj/16.21.6426Search 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, 1872–1877.10.1074/jbc.M309525200Search 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, 4531–4541.10.1038/sj.onc.1203806Search 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, 2930–2942.10.1038/sj.onc.1203612Search 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, 9–20.10.1016/S1383-5742(03)00033-4Search 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, 657–665.10.1038/nrm1175Search 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, 9294–9306.10.1128/MCB.20.24.9294-9306.2000Search in Google Scholar

Hahn, W.C. and Weinberg, R.A. (2002). Modelling the molecular circuitry of cancer. Nat. Rev. Cancer2, 331–341.10.1038/nrc795Search 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, 1306–1314.10.1021/bi972032dSearch 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, 2045–2057.10.1101/gad.993902Search in Google Scholar

Hamilton, M. and Wolfman, A. (1998). Ha-ras and N-ras regulate MAPK activity by distinct mechanisms in vivo. Oncogene16, 1417–1428.10.1038/sj.onc.1201653Search 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, 1318–1323.10.1128/MCB.15.3.1318Search in Google Scholar

Hancock, J.F. (2003). Ras proteins: different signals from different locations. Nat. Rev. Mol. Cell Biol.4, 373–384.10.1038/nrm1105Search 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–S31.10.1016/S1471-4914(02)02307-9Search in Google Scholar

Herrmann, C. (2003). Ras-effector interactions: after one decade. Curr. Opin. Struct. Biol.13, 122–129.10.1016/S0959-440X(02)00007-6Search 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, 335–342.10.1016/0092-8674(92)90361-FSearch in Google Scholar

Hruban, R.H., Wilentz, R.E., and Kern, S.E. (2000). Genetic progression in the pancreatic ducts. Am. J. Pathol.156, 1821–1825.10.1016/S0002-9440(10)65054-7Search 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, 473–483.10.1093/emboj/16.3.473Search in Google Scholar PubMed PubMed Central

Huang, C., Jacobson, K., and Schaller, M.D. (2004). MAP kinases and cell migration. J. Cell Sci.117, 4619–4628.10.1242/jcs.01481Search in Google Scholar PubMed

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, 125–136.10.1083/jcb.200108035Search in Google Scholar PubMed PubMed Central

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, 299–313.10.1083/jcb.200109037Search in Google Scholar PubMed PubMed Central

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, 5565–5576.10.1128/MCB.24.12.5565-5576.2004Search in Google Scholar PubMed PubMed Central

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, 1522–1535.10.1091/mbc.01-11-0552Search in Google Scholar PubMed PubMed Central

Johnson, G.L. and Lapadat, R. (2002). Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science298, 1911–1912.10.1126/science.1072682Search in Google Scholar PubMed

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, 1111–1116.10.1038/35074129Search in Google Scholar PubMed

Kelley, G.G., Reks, S.E., Ondrako, J.M., and Smrcka, A.V. (2001). Phospholipase C(epsilon): a novel Ras effector. EMBO J.20, 743–754.10.1093/emboj/20.4.743Search 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, 3923–3933.10.1128/MCB.16.7.3923Search 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, 180–183.10.1038/24184Search in Google Scholar

Kjoller, L. and Hall, A. (1999). Signaling to Rho GTPases. Exp. Cell Res.253, 166–179.10.1006/excr.1999.4674Search 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, 481–492.10.1083/jcb.137.2.481Search in Google Scholar

Kloog, Y. and Cox, A.D. (2000). Ras inhibitors: potential for cancer therapeutics. Mol. Med. Today6, 398–402.10.1016/S1357-4310(00)01789-5Search 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, 253–261.10.1016/j.semcancer.2004.04.004Search in Google Scholar PubMed

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, 1151–1159.10.1038/sj.onc.1201284Search in Google Scholar PubMed

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, 457–470.10.1083/jcb.149.2.457Search in Google Scholar PubMed PubMed Central

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, 607–610.10.1074/jbc.271.2.607Search in Google Scholar PubMed

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, 621–625.10.1038/ncb833Search in Google Scholar

Lange-Carter, C.A. and Johnson, G.L. (1994). Ras-dependent growth factor regulation of MEK kinase in PC12 cells. Science265, 1458–1461.10.1126/science.8073291Search 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, 26802–26806.10.1074/jbc.270.45.26802Search 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, 31871–37878.10.1074/jbc.M301931200Search in Google Scholar

Lozano, E., Betson, M., and Braga, V.M. (2003). Tumor progression: small GTPases and loss of cell-cell adhesion. Bioessays25, 452–463.10.1002/bies.10262Search 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, 257–262.10.1016/S1535-6108(03)00248-4Search 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, 53–62.10.3892/ijo.14.1.53Search in Google Scholar PubMed

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, 867–871.10.1038/nature00848Search in Google Scholar PubMed

Malumbres, M. and Barbacid, M. (2003). RAS oncogenes: the first 30 years. Nat. Rev. Cancer3, 459–465.10.1038/nrc1097Search in Google Scholar PubMed

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, 4572–4581.10.1074/jbc.M209807200Search in Google Scholar PubMed

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, 2742–2750.10.1158/1078-0432.CCR-03-0149Search 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, 2092–2105.10.1093/emboj/18.8.2092Search 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, 314–319.10.1159/000055830Search 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, 53–62.10.1016/0092-8674(95)90370-4Search in Google Scholar

Nobes, C.D. and Hall, A. (1999). Rho GTPases control polarity, protrusion, and adhesion during cell movement. J. Cell Biol.144, 1235–1244.10.1083/jcb.144.6.1235Search in Google Scholar

Noren, N.K., Arthur, W.T., and Burridge, K. (2003). Cadherin engagement inhibits RhoA via p190RhoGAP. J. Biol. Chem.278, 13615–13618.10.1074/jbc.C200657200Search 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, 41–47.10.1016/S0959-437X(00)00154-4Search 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, 336–347.10.1091/mbc.01-02-0302Search 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, 368–375.10.1038/35070050Search in Google Scholar PubMed

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, 165–170.10.1083/jcb.200209091Search in Google Scholar PubMed PubMed Central

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–C163.10.1152/ajpcell.00142.2003Search 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, 6434–6442.10.1038/sj.onc.1203026Search in Google Scholar

Raftopoulou, M. and Hall, A. (2004). Cell migration: Rho GTPases lead the way. Dev. Biol.265, 23–32.10.1016/j.ydbio.2003.06.003Search 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, 471–477.10.1016/S0962-8924(01)02153-5Search in Google Scholar

Ridley, A.J. (2004). Rho proteins and cancer. Breast Cancer Res. Treat.84, 13–19.10.1023/B:BREA.0000018423.47497.c6Search 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, 1704–1709.10.1126/science.1092053Search in Google Scholar PubMed

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, 527–532.10.1038/370527a0Search in Google Scholar PubMed

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, 7052–7063.10.1128/MCB.18.12.7052Search in Google Scholar PubMed PubMed Central

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, 98–105.10.1038/10067Search in Google Scholar PubMed

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, 5128–5140.10.1128/MCB.22.14.5128-5140.2002Search in Google Scholar PubMed PubMed Central

Sahai, E. and Marshall, C.J. (2002). Rho-GTPases and cancer. Nat. Rev. Cancer2, 133–142.10.1038/nrc725Search 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, 755–766.10.1093/emboj/20.4.755Search 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, 1302–1308.10.1016/S0959-8049(99)00145-8Search 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, 333–338.10.1126/science.277.5324.333Search in Google Scholar

Sebti, S.M. and Adjei, A.A. (2004). Farnesyltransferase inhibitors. Semin. Oncol.31, 28–39.10.1053/j.seminoncol.2003.12.012Search 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, 593–602.10.1016/S0092-8674(00)81902-9Search 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, 949–960.10.1016/S0092-8674(00)80486-9Search 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, 147–154.10.1016/S0962-8924(00)01740-2Search in Google Scholar

Silvius, J.R. (2002). Mechanisms of ras protein targeting in mammalian cells. J. Membr. Biol.190, 83–92.10.1007/s00232-002-1026-4Search 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, 465–475.10.1016/0092-8674(87)90449-1Search 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, 5994–5999.10.1038/sj.onc.1207798Search 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, 3835–3846.10.1242/jcs.00679Search in Google Scholar

Takai, Y., Sasaki, T., and Matozaki, T. (2001). Small GTP-binding proteins. Physiol. Rev.81, 153–208.10.1152/physrev.2001.81.1.153Search 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, 1881–1891.10.1128/MCB.19.3.1881Search 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, 10983–10985.10.1073/pnas.211430998Search 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, 30362–30370.10.1074/jbc.272.48.30362Search in Google Scholar

Treisman, R. (1996). Regulation of transcription by MAP kinase cascades. Curr. Opin. Cell Biol.8, 205–215.10.1016/S0955-0674(96)80067-6Search in Google Scholar

Vanhaesebroeck, B. and Alessi, D.R. (2000). The PI3K-PDK1 connection: more than just a road to PKB. Biochem. J.346, 561–576.10.1042/bj3460561Search 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, 161–170.10.1136/jmg.2003.015339Search in Google Scholar PubMed PubMed Central

Vavvas, D., Li, X., Avruch, J., and Zhang, X.F. (1998). Identification of Nore1 as a potential Ras effector. J. Biol. Chem.273, 5439–5442.10.1074/jbc.273.10.5439Search in Google Scholar PubMed

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, 5291–5300.10.1158/0008-5472.CAN-04-1112Search in Google Scholar

Vivanco, I. and Sawyers, C.L. (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer2, 489–501.10.1038/nrc839Search 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, 17164–17170.10.1074/jbc.274.24.17164Search 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, 8773–8778.10.1073/pnas.95.15.8773Search 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, 2579–2588.10.1038/sj.onc.1202602Search 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, 1915–1922.10.2174/1381612043384402Search 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, 14459–14464.10.1074/jbc.272.22.14459Search 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, 471–474.10.1016/S0960-9822(98)70183-6Search 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, 24052–24056.10.1074/jbc.273.37.24052Search in Google Scholar PubMed

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, 30928–30936.10.1074/jbc.272.49.30928Search in Google Scholar PubMed

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, 27902–27907.10.1074/jbc.272.44.27902Search in Google Scholar PubMed

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, 5694–5701.10.1038/sj.onc.1206858Search in Google Scholar PubMed

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, 271–279.10.3892/ijo.15.2.271Search in Google Scholar PubMed

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, 992–997.10.1006/bbrc.2001.4243Search in Google Scholar PubMed

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, 775–782.10.1083/jcb.149.4.775Search in Google Scholar PubMed PubMed Central