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J Biol Chem, Vol. 273, Issue 32, 19925-19928, August 7, 1998

MINIREVIEW
Increasing Complexity of the Ras Signaling Pathway^*

Anne B. Vojtek and Channing J. Der^§¶

From the  Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109-0636 and ^§ Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599

	INTRODUCTION

Top Introduction References

Ras is a key regulator of cell growth in all eukaryotic cells. Genetic, biochemical, and molecular studies in Caenorhabditis elegans, Drosophila, and mammalian cells have positioned Ras centrally in signal transduction pathways that respond to diverse extracellular stimuli, including peptide growth factors, cytokines, and hormones. The biological activity of Ras is controlled by a regulated GDP/GTP cycle. Guanine nucleotide exchange factors (GEFs¹; RasGRF1/2 and Sos1/2) promote the formation of the active, GTP-bound form of Ras (1). GTPase-activating proteins (GAPs; p120 GAP and NF1) accelerate the intrinsic GTP hydrolytic activity of Ras to promote formation of the inactive, GDP-bound form of Ras (1). Mutations in Ras at amino acids 12, 13, or 61 make Ras insensitive to GAP action and, hence, constitutively active in transforming mammalian cells (2, 3). These activating mutations in Ras are prevalent in a wide spectrum of human cancers. It has been estimated that 30% of all human tumors contain an activating mutation in Ras. The frequency of Ras mutations varies depending on tumor type, with the highest frequencies seen in lung, colon, thyroid, and pancreatic carcinomas (3). The frequency of Ras mutations is likely to be an underestimation of the contribution of aberrant signaling through the Ras pathway to human malignancies because chronic up-regulation of the Ras pathway can occur in the absence of mutations in Ras itself (4-6).

	Ras Directly Binds Raf and Activates a Kinase Cascade

Ras mediates its effects on cellular proliferation in part by activation of a cascade of kinases: Raf (c-Raf-1, A-Raf, and B-Raf), MEK (MAPK/ERK kinases 1 and 2), and ERK1/2 (7). Upon activation, the ERKs phosphorylate cytoplasmic targets (such as Rsk (8) and Mnk (9, 10)) and translocate to the nucleus, where they stimulate the activity of various transcription factors that include the Elk-1 transcription factor (Fig. 1). Ras activates this kinase cascade by directly binding to Raf (11, 12). The binding of Ras to Raf requires active, GTP-bound Ras and an intact effector domain. The recent observation that Ras interacts with two distinct NH₂-terminal regions of Raf-1 (RID/RBS1, spanning residues 51-131 (13, 14) and Raf-CRD (14)) suggests that Ras promotes more than just membrane translocation of Raf and instead may also facilitate the subsequent events that lead to Raf-1 activation. Other components that contribute to Raf-1 activation include 14-3-3 proteins, phospholipids, and serine/threonine and tyrosine kinases (15). Therefore, the connection between Ras and Raf alone is not simply linear and requires multicomplex formation to complete Raf activation.

View larger version (66K): [in this window] [in a new window]   Fig. 1.   Ras regulates a cascade of kinases. Ras is a GDP/GTP-regulated binary switch that resides at the inner surface of the plasma membrane and acts to relay extracellular ligand-stimulated signals to cytoplasmic signaling cascades. A linear pathway where Ras functions downstream of receptor tyrosine kinases (RTK) and upstream of a cascade of serine/threonine kinases (Raf > MEK > ERK) provides a complete link between the cell surface and the nucleus. Activated ERKs can translocate into the nucleus to phosphorylate and activate transcription factors, such as Elk-1. Activated ERKs also phosphorylate substrates in the cytoplasm, including the Mnk kinase, and thus contribute to translation initiation of mRNAs with structured 5'-untranslated regions.

	Ras Targets Multiple Effectors

Ras is likely to act through additional proteins besides Raf. The earliest observations that Ras has multiple effector proteins came from genetic studies in the budding yeast Saccharomyces cerevisiae and later the fission yeast Schizosaccharomyces pombe. Budding yeast devoid of Ras function were inviable, but yeast lacking adenylyl cyclase, an effector of Ras in this organism, were often capable of forming slow growing microcolonies (16). This result suggested that Ras proteins in S. cerevisiae have an essential function other than the activation of adenylyl cyclase. In S. pombe, Ras directly interacts with two effectors: Byr2, a MAPK kinase kinase, and Scd1, a GEF for the Rho family protein Cdc42 (17). Three additional observations in mammalian cells indicated that the events downstream of Ras are more complex than simply activating the Raf kinase. First, activated Raf induces only a subset of the events mediated by activated Ras. For example, activated Ras activates three distinct MAPK cascades (ERK, JNK, p38), whereas Raf causes direct activation only of ERK (18, 19). Second, activated Raf is not sufficient to promote all functions of Ras, such as the transformation of some epithelial cells (20). Third, studies with Ras mutants that discriminate between effectors suggest that multiple effector-mediated pathways are important for establishing and maintaining the transformed state (21, 48).

A plethora of candidate Ras effectors in addition to Raf have been reported. These include p120 Ras GAP (22), GEFs for the small GTPase Ral (RalGDS, RGL, RLF/RGL2) (23), AF6/Canoe (24, 25), RIN1 (26), and phosphatidylinositol 3-kinase (PI3K) (27). Although these candidate effectors comprise a very diverse collection of structurally and functionally distinct proteins, they all show preferential affinity for active Ras-GTP. Therefore, it is not surprising that residues corresponding to the switch I (Ras residues 30-37) and II (residues 59-76), which define the conformation differences between the GDP- and GTP-bound Ras, are involved in effector recognition. Specifically, an intact core Ras effector domain (residues 32-40) is essential for all effector interactions. Mutation of residues in sequences flanking this region (spanning residues 25-45) show differential impairment of effector interactions and provide useful mutants to decipher the contribution of specific effectors for Ras function (28). Thus, Ras residues important for effector interaction are more extensive than originally believed. The interaction of Ras with candidate effectors is often direct (interaction is observed in vitro using proteins purified from bacteria). For some, the interaction with Ras is observed in vivo upon co-immunoprecipitation, but these experiments are often done under conditions in which the Ras target is overexpressed. To date, Raf is the only Ras target protein for which genetic studies confirm its fundamental role in Ras signaling in a normal cellular context. Nonetheless, the interaction of Ras with at least some of these target proteins is likely to be critical for mediating the role of oncogenic Ras in malignant transformation.

	Multiple Effector Pathways Contribute to Ras-mediated Transformation

What is the contribution of each of the known effector-mediated pathways to malignant transformation? The current state of affairs is depicted in Fig. 2. As described earlier, activation of the Raf/ERK pathway, with its concomitant activation of transcription factors, is essential for cell proliferation. The Ras GTPase-activating protein, p120 GAP, in addition to negatively regulating Ras function may impinge on the Rho family via its association with p190, a GAP for Rho family members (29). Activation of members of the Rho family of GTPases is likely to contribute significantly to the Ras-transformed phenotype (reviewed in Ref. 30).

View larger version (17K): [in this window] [in a new window]   Fig. 2.   A surfeit of candidate Ras effectors. Multiple effector pathways contribute to Ras function. Our current understanding of the downstream targets of each of the Ras effectors is shown in the figure (see text for details). PLD, phospholipase D; PIP3, phosphatidylinositol trisphosphate; MEKK, MEK kinase; SEK, SAPK/JNK kinase; SRF, serum response factor.

The family of GEFs for Ral have also been implicated as target proteins for Ras (31, 32). A role for Ral in regulation of phospholipase D and in actin cytoskeletal rearrangements (via interaction with RalBP1) has been suggested (33, 34). In one report, RalA has been reported to cooperate with Ras for transformation (35), but others have not seen this cooperativity (36). Perhaps the RalGDS targets other proteins in addition to Ral that can influence the transformed phenotype. There is precedence for multiple functions residing in GEFs; SOS facilitates the exchange of nucleotides on Ras and couples Ras to Rac through its Dbl and pleckstrin homology (PH) domains in a PI3K-dependent manner (37).

RIN1 was identified in a genetic selection for mammalian cDNAs that were capable of suppressing the phenotypes associated with constitutive activation of the Ras pathway in S. cerevisiae (38). RIN1 interacts directly with Ras in a GTP- and effector domain-dependent fashion and localizes to the plasma membrane (26). Subsequently, RIN1 was shown to interact with Abl and Bcr/Abl in vitro and in vivo through a domain distinct from the Ras binding domain (39, 40). Moreover, RIN1 can enhance the transforming activity of Bcr/Abl and rescue several transformation-defective mutants of Bcr/Abl (40). The aspects of Ras function mediated by RIN1 are still the subject of investigation, but one possibility is that RIN1 coordinates signals from Ras and Abl.

Biochemically, AF6/Canoe are candidate Ras effectors (25). In addition, genetic studies in Drosophila have linked Canoe to Ras in eye development (41). Canoe/AF6 have a GLG(F/D)HR motif, a conserved sequence found in proteins that associate with cellular junctions, so perhaps Canoe/AF6 coordinate signaling events at the plasma membrane to remodeling of the actin cytoskeleton.

Finally, activation of PI3K, via a direct interaction between Ras and the catalytic subunit of the protein, is necessary for actin cytoskeletal rearrangements associated with the transformed phenotype (36). PI3K is a lipid kinase with specificity for the 3-position of the inositol ring. Activation of PI3K by a variety of extracellular stimuli leads to the accumulation of the second messenger phosphatidylinositol 3,4,5-trisphosphate. What are the downstream targets of this second messenger? One target is the serine/threonine kinase Akt/PKB. Binding of Akt/PKB via its PH domain to phosphatidylinositol 3,4,5-trisphosphate localizes Akt/PKB to the plasma membrane and leads to a partial activation of its kinase activity (42). Akt/PKB activity is further increased by phosphorylation on 2 residues by two different kinases, one of which, PDK1, is itself a lipid-regulated kinase (43). The events downstream of Akt/PKB are the subject of intense investigation in many laboratories. Akt/PKB phosphorylates and inactivates the pro-apoptotic protein BAD (44, 45) but is likely to have additional substrates. Other targets of the products of PI3K include the PH domains of Vav (46), SOS (37), and GRP1 (47).

One of the more elegant approaches to understanding the contribution of each of the effector pathways to Ras-mediated transformation has been the use of Ras effector mutants that are impaired in binding a specific target (21, 36, 48, 49). For example, studies with effector domain mutants have revealed a bifurcation of the signaling pathways downstream of Ras leading to remodeling of the actin cytoskeleton and DNA synthesis. RasV12C40, an activated mutant of Ras with an alteration of tyrosine to cysteine at position 40 in the effector domain, is unable to bind Raf. This mutant fails to activate the ERK cascade and cannot activate a Ras-responsive reporter construct, but it is capable of inducing membrane ruffling to the same extent as an activated Ras with an intact effector domain (49). These results suggest that stimulation of membrane ruffling and activation of the ERK cascade are mediated by distinct Ras effector proteins. Subsequently, RasV12C40 was shown to bind to and activate PI3K, suggesting that Ras-induced morphological alterations may be mediated in part through activation of PI3K (36). In addition to binding PI3K, RasV12C40 will also interact with AF6 (48), and a role for AF6 in modulation of the actin cytoskeleton by RasV12C40 cannot be excluded. Finally, the ability of this mutant to cause tumorigenic transformation demonstrates that Raf-independent pathways alone are sufficient to promote Ras transformation.

Two additional approaches to dissect the contributions of this surfeit of candidate effector proteins to Ras function have been to overexpress or membrane-target a specific effector to see if this mimics any aspect of Ras function. Targeting to the plasma membrane is often achieved by adding the sequence containing the CAAX box of Ras to the effector of interest. Membrane targeting has been shown to cause constitutive activation of Raf and PI3K. If membrane targeting of the candidate effector does not reproduce any aspect of Ras function, it may be that the target protein under study is already constitutively localized in this cellular compartment. Although Raf and PI3K reside in the cytoplasm and become associated with the plasma membrane upon receipt of stimulatory signal(s), other Ras target proteins, such as adenylyl cyclase in yeast and the RalGDS, are constitutively membrane localized. Membrane-targeted RalGDS did not exhibit any transforming potential.² Finally, a powerful (but as yet not common) approach to decipher the role of a Ras target protein is to determine whether fibroblasts derived from mice deficient in a target protein are impaired in transformation (for example, see Ref. 50).

	Ras Mediates Life and Death Decisions by Distinct Effector Pathways

One perplexing aspect of the Ras signaling pathway is that Ras can promote both cell death and cell survival through interactions with distinct effector proteins. Using Ras mutants, Kauffmann-Zeh et al. (51) demonstrated that activation of Raf by Ras promotes apoptosis in fibroblasts containing an inducible c-Myc oncoprotein, whereas activation of PI3K by Ras promotes cell survival. In this assay, oncogenic Ras enhanced apoptosis. This result suggests that Ras has the potential to trigger two seemingly contradictory biological outcomes: cell death by activation of Raf and cell survival by activation of PI3K. At least in this assay system, cell death (the Raf pathway) is dominant over cell survival (the PI3K pathway). How this seemingly discordant choice of cell death versus survival is achieved is not known.

What is the contribution of each of these pathways to tumor initiation and/or progression? Promotion of cell death by activation of Raf may be an important factor in limiting the expansion of cells harboring Ras mutations, whereas promotion of cell survival by activation of PI3K may contribute to tumor expansion and metastases. It will be interesting to see if the relative contributions of these antagonistic pathways can be modulated by other signaling pathways and whether such modulation plays a role in tumor formation.

Activated Ras also promotes cell survival in epithelial cells upon detachment from an extracellular matrix (52). This action of Ras is mediated through activation of PI3K and Akt/PKB. Given that the majority of human tumors are of epithelial cell origin, a pharmacological intervention that could switch a Ras-dependent survival signal into an apoptotic signal might be of considerable value in the treatment of human malignancies.

	Summary

The last 5 years have seen an impressive expansion in the number of candidate Ras effectors. Much progress has been made toward deciphering the aspects of Ras function mediated by each of these proteins, and many studies, in particular those with effector domain mutants, have convincingly demonstrated that Ras must target at least three different pathways for transformation. The corruption of the signaling pathways that lie downstream of Ras is a recurring theme in the initiation and/or progression of human malignancies. Pharmacological interventions have directly impeded Ras function by interfering with its farnesylation and membrane targeting or have blocked activation of components of the kinase cascade downstream of Ras (53). However, the function of Ras and its downstream kinase cascade is central to many cellular processes, and this may limit the usefulness of these approaches. The diversity of Ras target proteins and the necessity for activation of multiple effector pathways for malignant transformation by Ras open new directions for the design of additional therapeutic interventions that may negate Ras transformation without abolishing all of Ras function.

	ACKNOWLEDGEMENTS

We thank Adrienne Cox and John Colicelli for helpful comments and Jennifer Parrish for assistance in figure and manuscript preparations.

	FOOTNOTES

^* This minireview will be reprinted in the 1998 Minireview Compendium, which will be available in December, 1998. This is the first article of five in the "Small GTPases Minireview Series."

^¶ To whom correspondence should be addressed. Tel.: 919-966-5634; Fax: 919-966-0162.

The abbreviations used are: GEF, guanine nucleotide exchange factor; GAP, GTPase-activating protein; MAPK, mitogen-activated protein kinase; ERK, extracellular receptor-stimulated kinase; MEK, MAPK/ERK kinase; RID, Ras-interaction domain; RBS, Ras-binding site; CRD, cysteine-rich domain; JNK, Jun NH₂-terminal kinasePI3K, phosphatidylinositol 3-kinasePH, pleckstrin homologyCAAX, cysteine, aliphatic, aliphatic, terminal amino acid.

² G. J. Clark and C. J. Der, unpublished observation.

	REFERENCES

Top Introduction References

1. Bourne, H., Sanders, D., and McCormick, F. (1991) Nature 349, 117-127[CrossRef][Medline] [Order article via Infotrieve]
2. Bos, J. L. (1989) Cancer Res. 49, 4682-4689[Abstract/Free Full Text]
3. Clark, G. J., and Der, C. J. (1993) in GTPases in Biology (Dickey, B. F., and Birnbaumer, L., eds), pp. 259-288, Springer-Verlag, Berlin
4. Ben-Levy, R., Paterson, H. F., Marshall, C. J., and Yarden, Y. (1994) EMBO J. 13, 3302-3311[Medline] [Order article via Infotrieve]
5. Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., and McGuire, W. L. (1987) Science 235, 177-182[Abstract/Free Full Text]
6. DeClue, J. E., Papageorge, A. G., Fletcher, J. A., Diehl, S., Ratner, N., Vass, W. C., and Lowy, D. L. (1992) Cell 69, 265-273[CrossRef][Medline] [Order article via Infotrieve]
7. Egan, S. E., and Weinberg, R. A. (1993) Nature 365, 781-783[CrossRef][Medline] [Order article via Infotrieve]
8. Sturgill, T. W., Ray, L. B., Erikson, E., and Maller, J. L. (1988) Nature 334, 715-718[CrossRef][Medline] [Order article via Infotrieve]
9. Waskiewicz, A. J., Flynn, A. F., Proud, C. G., and Cooper, J. A. (1997) EMBO J. 16, 1909-1920[CrossRef][Medline] [Order article via Infotrieve]
10. Wang, X., Flynn, A. F., Waskiewicz, A. J., Webb, B. L. J., Vries, R. G., Baines, I. A., Cooper, J. A., and Proud, C. G. (1998) J. Biol. Chem. 273, 9373-9377[Abstract/Free Full Text]
11. Vojtek, A. B., Hollenberg, S. M., and Cooper, J. A. (1993) Cell 74, 205-214[CrossRef][Medline] [Order article via Infotrieve]
12. Warne, P., Rodruguez-Viciana, P., and Downward, J. (1993) Nature 364, 352-356[CrossRef][Medline] [Order article via Infotrieve]
13. Fabian, J. R., Vojtek, A. B., Cooper, J. A., and Morrison, D. K. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 5982-5986[Abstract/Free Full Text]
14. Brtva, T. R., Drugan, J. K., Ghosh, S., Terrell, R. S., Campbell-Burk, S., Bell, R. M., and Der, C. J. (1995) J. Biol. Chem. 270, 9809-9812[Abstract/Free Full Text]
15. Morrison, D. K., and Cutler, R. E. (1997) Curr. Opin. Cell Biol. 9, 174-179[CrossRef][Medline] [Order article via Infotrieve]
16. Toda, T., Broek, D., Field, J., Michaeli, T., Cameron, S., Nikawa, J., Sass, P., Birchmeier, C., Powers, S., and Wigler, M. (1987) in Oncogenes and Cancer (Aaronson, S. A., ed), pp. 253-260, Japan Scientific Society Press, Tokyo/VNU Scientific Press, Utrecht
17. Chang, E. C., Barr, M., Wang, Y. U., Jung, V., Xu, H. P., and Wigler, M. (1994) Cell 79, 131-141[CrossRef][Medline] [Order article via Infotrieve]
18. Minden, A., Lin, A., Claret, F.-X., Abo, A., and Karin, M. (1995) Cell 81, 1147-1157[CrossRef][Medline] [Order article via Infotrieve]
19. Olson, M. F., Ashworth, A., and Hall, A. (1995) Science 269, 1270-1272[Abstract/Free Full Text]
20. Oldham, S. M., Clark, G. J., Gangarosa, L. M., Coffey, R. J., Jr., and Der, C. J. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 6924-6928[Abstract/Free Full Text]
21. White, M. A., Nicolette, C., Minden, A., Polverino, A., Van Aelst, L., Karin, M., and Wigler, M. (1995) Cell 80, 533-541[CrossRef][Medline] [Order article via Infotrieve]
22. Yatani, A., Okabe, K., Polakis, P., Halenbeck, R., McCormick, F., and Brown, A. M. (1990) Cell 61, 769-776[CrossRef][Medline] [Order article via Infotrieve]
23. Feig, L. A., Urano, T., and Cantor, S. (1996) Trends Biochem. Sci. 21, 438-441[CrossRef][Medline] [Order article via Infotrieve]
24. Van Aelst, L., White, M. A., and Wigler, M. H. (1994) Cold Spring Harbor Symp. Quant. Biol. 59, 181-186[Abstract/Free Full Text]
25. Kuriyama, M., Harada, N., Kuroida, S., Yammato, T., Nakafuku, M., Iwamatsu, A., Yamamoto, D., Prasad, R., Croce, C., Canaani, E., and Kaibuchi, K. (1996) J. Biol. Chem. 271, 607-610[Abstract/Free Full Text]
26. Han, L., and Colicelli, J. (1995) Mol. Cell. Biol. 15, 1318-1323[Abstract]
27. Rodriguez-Viciana, P., Warne, P. H., Dhand, R., Vanhaesebroeck, B., Gout, I., Fry, M. J., Waterfield, M. D., and Downward, J. (1994) Nature 370, 527-552[CrossRef][Medline] [Order article via Infotrieve]
28. Winkler, D. G., Johnson, J. C., Cooper, J. A., and Vojtek, A. B. (1997) J. Biol. Chem. 272, 24402-24409[Abstract/Free Full Text]
29. Settleman, J., Narasimhan, V., Foster, L. C., and Weinberg, R. A. (1992) Cell 69, 539-549[CrossRef][Medline] [Order article via Infotrieve]
30. Zohn, I., Campbell, S., Khosravi-Far, R., Rossman, K. L., and Der, C. J. (1998) Oncogene, in press
31. Hofer, F., Fields, S., Schneider, C., and Martin, G. (1994) Proc. Natl. Acad. Sci. U. S. A. 11089-11093
32. Kikuchi, A., Demo, S., Ye, Z., Chen, Y.-W., and Williams, L. T. (1994) Mol. Cell. Biol. 14, 7483-7491[Abstract/Free Full Text]
33. Jiang, H., Luo, J.-Q., Urano, T., Frankel, P., Lu, Z., Foster, D. A., and Feig, L. A. (1995) Nature 378, 409-412[CrossRef][Medline] [Order article via Infotrieve]
34. Cantor, S., Urano, T., and Feig, L. A. (1995) Mol. Cell. Biol. 15, 4578-4584[Abstract]
35. Urano, T., Emkey, R., and Feig, L. A. (1996) EMBO J. 15, 810-816[Medline] [Order article via Infotrieve]
36. Rodriguez-Viciana, P., Warne, P. H., Khwaja, A., Marte, B. M., Pappin, D., Das, P., Waterfield, M. D., Ridley, A., and Downward, J. (1997) Cell 89, 457-467[CrossRef][Medline] [Order article via Infotrieve]
37. Nimnual, A. S., Yatsula, B. A., and Bar-Sagi, D. (1998) Science 279, 560-563[Abstract/Free Full Text]
38. Colicelli, J., Nicolette, C., Birchmeier, C., Rodgers, L., Riggs, M., and Wigler, M. (1991) Proc. Natl. Acad. Sci. U. S. A. 88, 2913-2917[Abstract/Free Full Text]
39. Han, L., Wong, D., Dhaka, A., Afar, D., White, M., Xie, W., Herschman, H., Witte, O., and Colicelli, J. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 4954-4959[Abstract/Free Full Text]
40. Afar, D. E., Han, L., McLaughlin, J., Wong, S., Dhaka, A., Parmar, K., Rosenberg, N., Witte, O. N., and Colicelli, J. Immunity 6, 773-782
41. Matsuo, T., Takahashi, K., Kondo, S., Kaibuchi, K., and Yamamoto, D. (1997) Development 124, 2671-2680[Abstract]
42. Hemmings, B. A. (1997) Science 275, 628-630[Free Full Text]
43. Stephens, L., Anderson, K., Stokoe, D., Erkjument-Bromage, H., Painter, G. F., Holmes, A. B., Gaffney, P. R. J., Reese, C. B., McCormick, F., Tempst, P., Coadwell, J., and Hawkins, P. T. (1998) Science 279, 710-714[Abstract/Free Full Text]
44. del Peso, L., Gonzalez-Garcia, M., Page, C., Herrera, R., and Nunez, G. (1997) Science 278, 687-689[Abstract/Free Full Text]
45. Datta, S. R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, K., and Greenberg, M. E. (1997) Cell 91, 231-241[CrossRef][Medline] [Order article via Infotrieve]
46. Han, J., Luby-Phelps, K., Das, B., Shu, X., Xia, Y., Mosteller, R. D., Krishna, U. M., Falck, J. R., White, M. A., and Broek, D. (1998) Science 279, 558-560[Abstract/Free Full Text]
47. Klarlund, J. K., Guilherme, G., Holik, J. J., Virbasius, J. V., Chawla, A., and Czech, M. P. (1997) Science 275, 1927-1930[Abstract/Free Full Text]
48. Khosravi-Far, R., White, M. A., Westwick, J. D., Solski, P. A., Chrzanowska-Wodnicka, M., Van Aelst, L., Wigler, M. H., and Der, C. J. (1996) Mol. Cell. Biol. 16, 3923-3933[Abstract]
49. Joneson, T., White, M. A., Wigler, M. H., and Bar-Sagi, D. (1996) Science 271, 810-812[Abstract]
50. van der Geer, P., Henkmeyer, M., Jacks, T., and Pawson, T. (1997) Mol. Cell. Biol. 17, 1840-1847[Abstract]
51. Kauffmann-Zeh, A., Rodriguez-Viciana, P., Ulrich, E., Gilbert, C., Coffer, P., Downward, J., and Evan, G. (1997) Nature 385, 544-548[CrossRef][Medline] [Order article via Infotrieve]
52. Khwaja, A., Rodriguez-Viciana, P., Wennstrom, S., Warne, P. H., and Downward, J. (1997) EMBO J. 16, 2783-2793[CrossRef][Medline] [Order article via Infotrieve]
53. Cox, A. D., and Der, C. J. (1997) Biochim. Biophys. Acta Rev. Cancer 1333, F51-F71[Medline] [Order article via Infotrieve]

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				K. Subbaramaiah and A. J. Dannenberg Cyclooxygenase-2 Transcription Is Regulated by Human Papillomavirus 16 E6 and E7 Oncoproteins: Evidence of a Corepressor/Coactivator Exchange Cancer Res., April 15, 2007; 67(8): 3976 - 3985. [Abstract] [Full Text] [PDF]

				J. Cruz, A Ocana, E Del Barco, and A Pandiella Targeting receptor tyrosine kinases and their signal transduction routes in head and neck cancer Ann. Onc., March 1, 2007; 18(3): 421 - 430. [Abstract] [Full Text] [PDF]

				L. Goldberg and Y. Kloog A Ras Inhibitor Tilts the Balance between Rac and Rho and Blocks Phosphatidylinositol 3-Kinase-Dependent Glioblastoma Cell Migration Cancer Res., December 15, 2006; 66(24): 11709 - 11717. [Abstract] [Full Text] [PDF]

				G. Ghiaur, A. Lee, J. Bailey, J. A. Cancelas, Y. Zheng, and D. A. Williams Inhibition of RhoA GTPase activity enhances hematopoietic stem and progenitor cell proliferation and engraftment Blood, September 15, 2006; 108(6): 2087 - 2094. [Abstract] [Full Text] [PDF]

				A. Kiyatkin, E. Aksamitiene, N. I. Markevich, N. M. Borisov, J. B. Hoek, and B. N. Kholodenko Scaffolding Protein Grb2-associated Binder 1 Sustains Epidermal Growth Factor-induced Mitogenic and Survival Signaling by Multiple Positive Feedback Loops J. Biol. Chem., July 21, 2006; 281(29): 19925 - 19938. [Abstract] [Full Text] [PDF]

				K. T. Lane and L. S. Beese Thematic review series: Lipid Posttranslational Modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I J. Lipid Res., April 1, 2006; 47(4): 681 - 699. [Abstract] [Full Text] [PDF]

				F. G. Haluska, H. Tsao, H. Wu, F. S. Haluska, A. Lazar, and V. Goel Genetic alterations in signaling pathways in melanoma. Clin. Cancer Res., April 1, 2006; 12(7): 2301s - 2307s. [Abstract] [Full Text] [PDF]

				J. S. Krumenacker, A. Kots, and F. Murad Effects of the JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-one (SP-600125) on soluble guanylyl cyclase {alpha}1 gene regulation and cGMP synthesis Am J Physiol Cell Physiol, October 1, 2005; 289(4): C778 - C784. [Abstract] [Full Text] [PDF]

				M. Beeram, A. Patnaik, and E. K. Rowinsky Raf: A Strategic Target for Therapeutic Development Against Cancer J. Clin. Oncol., September 20, 2005; 23(27): 6771 - 6790. [Abstract] [Full Text] [PDF]

				M. Ye, F. Shima, S. Muraoka, J. Liao, H. Okamoto, M. Yamamoto, A. Tamura, N. Yagi, T. Ueki, and T. Kataoka Crystal Structure of M-Ras Reveals a GTP-bound "Off" State Conformation of Ras Family Small GTPases J. Biol. Chem., September 2, 2005; 280(35): 31267 - 31275. [Abstract] [Full Text] [PDF]

				B. Ford, K. Skowronek, S. Boykevisch, D. Bar-Sagi, and N. Nassar Structure of the G60A Mutant of Ras: IMPLICATIONS FOR THE DOMINANT NEGATIVE EFFECT J. Biol. Chem., July 8, 2005; 280(27): 25697 - 25705. [Abstract] [Full Text] [PDF]

				J. Tang, X. Qi, D. Mercola, J. Han, and G. Chen Essential Role of p38{gamma} in K-Ras Transformation Independent of Phosphorylation J. Biol. Chem., June 24, 2005; 280(25): 23910 - 23917. [Abstract] [Full Text] [PDF]

				A. Zampetaki, Z. Zhang, Y. Hu, and Q. Xu Biomechanical stress induces IL-6 expression in smooth muscle cells via Ras/Rac1-p38 MAPK-NF-{kappa}B signaling pathways Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2946 - H2954. [Abstract] [Full Text] [PDF]

				X. Zhu, J. Jiang, H. Shen, H. Wang, H. Zong, Z. Li, Y. Yang, Z. Niu, W. Liu, X. Chen, et al. Elevated {beta}1,4-Galactosyltransferase I in Highly Metastatic Human Lung Cancer Cells: IDENTIFICATION OF E1AF AS IMPORTANT TRANSCRIPTION ACTIVATOR J. Biol. Chem., April 1, 2005; 280(13): 12503 - 12516. [Abstract] [Full Text] [PDF]

				A. Chan Ras-MAPK Pathways Sci. Signal., February 15, 2005; 2005(271): tr5 - tr5. [Abstract] [Full Text] [PDF]

				B. Paul, C. S. Hayes, A. Kim, M. Athar, and S. K. Gilmour Elevated polyamines lead to selective induction of apoptosis and inhibition of tumorigenesis by (-)-epigallocatechin-3-gallate (EGCG) in ODC/Ras transgenic mice Carcinogenesis, January 1, 2005; 26(1): 119 - 124. [Abstract] [Full Text] [PDF]

				A.-L. Li, H.-Y. Li, B.-F. Jin, Q.-N. Ye, T. Zhou, X.-D. Yu, X. Pan, J.-H. Man, K. He, M. Yu, et al. A Novel eIF5A Complex Functions As a Regulator of p53 and p53-dependent Apoptosis J. Biol. Chem., November 19, 2004; 279(47): 49251 - 49258. [Abstract] [Full Text] [PDF]

				L. Klampfer, J. Huang, T. Sasazuki, S. Shirasawa, and L. Augenlicht Oncogenic Ras Promotes Butyrate-induced Apoptosis through Inhibition of Gelsolin Expression J. Biol. Chem., August 27, 2004; 279(35): 36680 - 36688. [Abstract] [Full Text] [PDF]

				C. Segrelles, S. Ruiz, M. Santos, J. Martinez-Palacio, M. F. Lara, and J. M. Paramio Akt mediates an angiogenic switch in transformed keratinocytes Carcinogenesis, July 1, 2004; 25(7): 1137 - 1147. [Abstract] [Full Text] [PDF]

				X. Qi, J. Tang, R. Pramanik, R. M. Schultz, S. Shirasawa, T. Sasazuki, J. Han, and G. Chen p38 MAPK Activation Selectively Induces Cell Death in K-ras-mutated Human Colon Cancer Cells through Regulation of Vitamin D Receptor J. Biol. Chem., May 21, 2004; 279(21): 22138 - 22144. [Abstract] [Full Text] [PDF]

				F. R. DANESH and Y. S. KANWAR Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy FASEB J, May 1, 2004; 18(7): 805 - 815. [Abstract] [Full Text] [PDF]

				S. Zhougang and R. G. Schnellmann H2O2-induced transactivation of EGF receptor requires Src and mediates ERK1/2, but not Akt, activation in renal cells Am J Physiol Renal Physiol, May 1, 2004; 286(5): F858 - F865. [Abstract] [Full Text] [PDF]

				B. Bedogni, M. S. O'Neill, S. M. Welford, D. M. Bouley, A. J. Giaccia, N. C. Denko, and M. B. Powell Topical Treatment with Inhibitors of the Phosphatidylinositol 3'-Kinase/Akt and Raf/Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Pathways Reduces Melanoma Development in Severe Combined Immunodeficient Mice Cancer Res., April 1, 2004; 64(7): 2552 - 2560. [Abstract] [Full Text] [PDF]

				G. Y.-P. Ko, M. L. Ko, and S. E. Dryer Circadian Regulation of cGMP-Gated Channels of Vertebrate Cone Photoreceptors: Role of cAMP and Ras J. Neurosci., February 11, 2004; 24(6): 1296 - 1304. [Abstract] [Full Text] [PDF]

				I. H. N. Wong, J. Chan, J. Wong, and P. K. H. Tam Ubiquitous Aberrant RASSF1A Promoter Methylation in Childhood Neoplasia1 Clin. Cancer Res., February 1, 2004; 10(3): 994 - 1002. [Abstract] [Full Text] [PDF]

				J. Sanchez-Esteban, Y. Wang, P. A. Gruppuso, and L. P. Rubin Mechanical Stretch Induces Fetal Type II Cell Differentiation Via an Epidermal Growth Factor Receptor-Extracellular-Regulated Protein Kinase Signaling Pathway Am. J. Respir. Cell Mol. Biol., January 1, 2004; 30(1): 76 - 83. [Abstract] [Full Text] [PDF]

				M. Hoshino and S. Nakamura Small GTPase Rin induces neurite outgrowth through Rac/Cdc42 and calmodulin in PC12 cells J. Cell Biol., December 8, 2003; 163(5): 1067 - 1076. [Abstract] [Full Text] [PDF]

				S. Lebreton, L. Boissel, and J. Moreau Control of embryonic Xenopus morphogenesis by a Ral-GDS/Xral branch of the Ras signalling pathway J. Cell Sci., November 15, 2003; 116(22): 4651 - 4662. [Abstract] [Full Text] [PDF]

				S. A. Holstein and R. J. Hohl Monoterpene regulation of Ras and Ras-related protein expression J. Lipid Res., June 1, 2003; 44(6): 1209 - 1215. [Abstract] [Full Text] [PDF]

				K. Shimizu, M. Okada, K. Nagai, and Y. Fukada Suprachiasmatic Nucleus Circadian Oscillatory Protein, a Novel Binding Partner of K-Ras in the Membrane Rafts, Negatively Regulates MAPK Pathway J. Biol. Chem., April 18, 2003; 278(17): 14920 - 14925. [Abstract] [Full Text] [PDF]

				G. D. Carystinos, M. Kandouz, M. A. Alaoui-Jamali, and G. Batist Unexpected Induction of the Human Connexin 43 Promoter by the Ras Signaling Pathway Is Mediated by a Novel Putative Promoter Sequence Mol. Pharmacol., April 1, 2003; 63(4): 821 - 831. [Abstract] [Full Text] [PDF]

				I. S. Long, K. Han, M. Li, S. Shirasawa, T. Sasazuki, M. Johnston, and M.-S. Tsao Met Receptor Overexpression and Oncogenic Ki-ras Mutation Cooperate to Enhance Tumorigenicity of Colon Cancer Cells in Vivo Mol. Cancer Res., March 1, 2003; 1(5): 393 - 401. [Abstract] [Full Text] [PDF]

				L. Zhao, S. Lobo, X. Dong, A. D. Ault, and R. J. Deschenes Erf4p and Erf2p Form an Endoplasmic Reticulum-associated Complex Involved in the Plasma Membrane Localization of Yeast Ras Proteins J. Biol. Chem., December 13, 2002; 277(51): 49352 - 49359. [Abstract] [Full Text] [PDF]

				S. K. NagDas, V. P. Winfrey, and G. E. Olson Identification of Ras and Its Downstream Signaling Elements and Their Potential Role in Hamster Sperm Motility Biol Reprod, October 1, 2002; 67(4): 1058 - 1066. [Abstract] [Full Text] [PDF]

				D. Wang, Z. Li, E. M. Messing, and G. Wu Activation of Ras/Erk Pathway by a Novel MET-interacting Protein RanBPM J. Biol. Chem., September 20, 2002; 277(39): 36216 - 36222. [Abstract] [Full Text] [PDF]

				B. E. Hall, D. Bar-Sagi, and N. Nassar The structural basis for the transition from Ras-GTP to Ras-GDP PNAS, September 17, 2002; 99(19): 12138 - 12142. [Abstract] [Full Text] [PDF]

				R. K. Strair, D. Schaar, L. Goodell, J. Aisner, K.-V. Chin, J. Eid, R. Senzon, X. X. Cui, Z. T. Han, B. Knox, et al. Administration of a Phorbol Ester to Patients with Hematological Malignancies: Preliminary Results from a Phase I Clinical Trial of 12-O-Tetradecanoylphorbol-13-acetate Clin. Cancer Res., August 1, 2002; 8(8): 2512 - 2518. [Abstract] [Full Text] [PDF]

				S. P. M. Reddy, P. Adiseshaiah, P. Shapiro, and H. Vuong BMK1 (ERK5) Regulates Squamous Differentiation Marker SPRR1B Transcription in Clara-like H441 Cells Am. J. Respir. Cell Mol. Biol., July 1, 2002; 27(1): 64 - 70. [Abstract] [Full Text] [PDF]

				K. Subbaramaiah, L. Norton, W. Gerald, and A. J. Dannenberg Cyclooxygenase-2 Is Overexpressed in HER-2/neu-positive Breast Cancer. EVIDENCE FOR INVOLVEMENT OF AP-1 AND PEA3 J. Biol. Chem., May 17, 2002; 277(21): 18649 - 18657. [Abstract] [Full Text] [PDF]

				A. K. Greenberg, S. Basu, J. Hu, T.-a. Yie, K. M. Tchou-Wong, W. N. Rom, and T. C. Lee Selective p38 Activation in Human Non-Small Cell Lung Cancer Am. J. Respir. Cell Mol. Biol., May 1, 2002; 26(5): 558 - 564. [Abstract] [Full Text] [PDF]

				C. E. Rocheleau, R. M. Howard, A. P. Goldman, M. L. Volk, L. J. Girard, and M. V. Sundaram A lin-45 raf Enhancer Screen Identifies eor-1, eor-2 and Unusual Alleles of Ras Pathway Genes in Caenorhabditis elegans Genetics, May 1, 2002; 161(1): 121 - 131. [Abstract] [Full Text] [PDF]

				W. Wu, I. Jaspers, W. Zhang, L. M. Graves, and J. M. Samet Role of Ras in metal-induced EGF receptor signaling and NF-kappa B activation in human airway epithelial cells Am J Physiol Lung Cell Mol Physiol, May 1, 2002; 282(5): L1040 - L1048. [Abstract] [Full Text] [PDF]

				V. Nancy, I. Callebaut, A. El Marjou, and J. de Gunzburg The delta Subunit of Retinal Rod cGMP Phosphodiesterase Regulates the Membrane Association of Ras and Rap GTPases J. Biol. Chem., April 19, 2002; 277(17): 15076 - 15084. [Abstract] [Full Text] [PDF]

				J. S. Russell, U. Raju, G. J. Gumin, F. F. Lang, D. R. Wilson, T. Huet, and P. J. Tofilon Inhibition of Radiation-induced Nuclear Factor-{kappa}B Activation by an Anti-Ras Single-Chain Antibody Fragment: Lack of Involvement in Radiosensitization Cancer Res., April 1, 2002; 62(8): 2318 - 2326. [Abstract] [Full Text] [PDF]

				S. A. Holstein, C. L. Wohlford-Lenane, and R. J. Hohl Consequences of Mevalonate Depletion. DIFFERENTIAL TRANSCRIPTIONAL, TRANSLATIONAL, AND POST-TRANSLATIONAL UP-REGULATION OF Ras, Rap1a, RhoA, AND RhoB J. Biol. Chem., March 15, 2002; 277(12): 10678 - 10682. [Abstract] [Full Text] [PDF]

				H. Kohler, S. P. Rodrigues, and B. A. McCormick Shigella flexneri Interactions with the Basolateral Membrane Domain of Polarized Model Intestinal Epithelium: Role of Lipopolysaccharide in Cell Invasion and in Activation of the Mitogen-Activated Protein Kinase ERK Infect. Immun., March 1, 2002; 70(3): 1150 - 1158. [Abstract] [Full Text] [PDF]

				E. Zentrich, S.-Y. Han, L. Pessoa-Brandao, L. Butterfield, and L. E. Heasley Collaboration of JNKs and ERKs in Nerve Growth Factor Regulation of the Neurofilament Light Chain Promoter in PC12 Cells J. Biol. Chem., February 1, 2002; 277(6): 4110 - 4118. [Abstract] [Full Text] [PDF]

				H. Vuong, T. Patterson, P. Adiseshaiah, P. Shapiro, D. V. Kalvakolanu, and S. P. M. Reddy JNK1 and AP-1 regulate PMA-inducible squamous differentiation marker expression in Clara-like H441 cells Am J Physiol Lung Cell Mol Physiol, February 1, 2002; 282(2): L215 - L225. [Abstract] [Full Text] [PDF]

				W. Che, J.-i. Abe, M. Yoshizumi, Q. Huang, M. Glassman, S. Ohta, M. G. Melaragno, V. Poppa, C. Yan, N. Lerner-Marmarosh, et al. p160 Bcr Mediates Platelet-Derived Growth Factor Activation of Extracellular Signal-Regulated Kinase in Vascular Smooth Muscle Cells Circulation, September 18, 2001; 104(12): 1399 - 1406. [Abstract] [Full Text] [PDF]

				N. Iida, K. Namikawa, H. Kiyama, H. Ueno, S. Nakamura, and S. Hattori Requirement of Ras for the Activation of Mitogen-Activated Protein Kinase by Calcium Influx, cAMP, and Neurotrophin in Hippocampal Neurons J. Neurosci., September 1, 2001; 21(17): 6459 - 6466. [Abstract] [Full Text] [PDF]

				M. J. Alcorn, J. L. Booth, K. M. Coggeshall, and J. P. Metcalf Adenovirus Type 7 Induces Interleukin-8 Production via Activation of Extracellular Regulated Kinase 1/2 J. Virol., July 15, 2001; 75(14): 6450 - 6459. [Abstract] [Full Text]

				R.G. Beniston, I.M. Morgan, V. O'Brien, and M.S. Campo Quercetin, E7 and p53 in papillomavirus oncogenic cell transformation Carcinogenesis, July 1, 2001; 22(7): 1069 - 1076. [Abstract] [Full Text] [PDF]

				J. Ho and A. Bretscher Ras Regulates the Polarity of the Yeast Actin Cytoskeleton through the Stress Response Pathway Mol. Biol. Cell, June 1, 2001; 12(6): 1541 - 1555. [Abstract] [Full Text] [PDF]

				F.-C. Yang, S. J. Atkinson, Y. Gu, J. B. Borneo, A. W. Roberts, Y. Zheng, J. Pennington, and D. A. Williams Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization PNAS, April 18, 2001; (2001) 101546898. [Abstract] [Full Text]

				A. Chiloeches, C. S. Mason, and R. Marais S338 Phosphorylation of Raf-1 Is Independent of Phosphatidylinositol 3-Kinase and Pak3 Mol. Cell. Biol., April 1, 2001; 21(7): 2423 - 2434. [Abstract] [Full Text]

				M. K. Topham and S. M. Prescott Diacylglycerol Kinase {zeta} Regulates Ras Activation by a Novel Mechanism J. Cell Biol., March 12, 2001; 152(6): 1135 - 1144. [Abstract] [Full Text] [PDF]

				A. Clerk, F. H. Pham, S. J. Fuller, E. Sahai, K. Aktories, R. Marais, C. Marshall, and P. H. Sugden Regulation of Mitogen-Activated Protein Kinases in Cardiac Myocytes through the Small G Protein Rac1 Mol. Cell. Biol., February 15, 2001; 21(4): 1173 - 1184. [Abstract] [Full Text]

				P. D. Ho, J.-S. Fan, N. L. Hayes, N. Saada, P. T. Palade, C. C. Glembotski, and P. M. McDonough Ras Reduces L-Type Calcium Channel Current in Cardiac Myocytes : Corrective Effects of L-Channels and SERCA2 on [Ca2+]i Regulation and Cell Morphology Circ. Res., January 19, 2001; 88(1): 63 - 69. [Abstract] [Full Text] [PDF]

				I. Prior and J. Hancock Compartmentalization of Ras proteins J. Cell Sci., January 5, 2001; 114(9): 1603 - 1608. [Abstract] [PDF]

				Y. Takai, T. Sasaki, and T. Matozaki Small GTP-Binding Proteins Physiol Rev, January 1, 2001; 81(1): 153 - 208. [Abstract] [Full Text] [PDF]

				N. Tamaoki The rasH2 Transgenic Mouse: Nature of the Model and Mechanistic Studies on Tumorigenesis Toxicol Pathol, January 1, 2001; 29(1_suppl): 81 - 89. [Abstract] [PDF]

				D. O. Henry, S. A. Moskalenko, K. J. Kaur, M. Fu, R. G. Pestell, J. H. Camonis, and M. A. White Ral GTPases Contribute to Regulation of Cyclin D1 through Activation of NF-kappa B Mol. Cell. Biol., November 1, 2000; 20(21): 8084 - 8092. [Abstract] [Full Text]

				L. Lan, C. Trempus, and S. K. Gilmour Inhibition of Ornithine Decarboxylase (ODC) Decreases Tumor Vascularization and Reverses Spontaneous Tumors in ODC/Ras Transgenic Mice Cancer Res., October 1, 2000; 60(20): 5696 - 5703. [Abstract] [Full Text]

				E M Fitzgerald Regulation of voltage-dependent calcium channels in rat sensory neurones involves a Ras-mitogen-activated protein kinase pathway J. Physiol., September 15, 2000; 527(3): 433 - 444. [Abstract] [Full Text] [PDF]

				I. J. Gonzalez-Robayna, A. E. Falender, S. Ochsner, G. L. Firestone, and J. S. Richards Follicle-Stimulating Hormone (FSH) Stimulates Phosphorylation and Activation of Protein Kinase B (PKB/Akt) and Serum and Glucocorticoid-Induced Kinase (Sgk): Evidence for A Kinase-Independent Signaling by FSH in Granulosa Cells Mol. Endocrinol., August 1, 2000; 14(8): 1283 - 1300. [Abstract] [Full Text]

				J. Suzuki, Y. Yamazaki, L. Guang, Y. Kaziro, and H. Koide Involvement of Ras and Ral in Chemotactic Migration of Skeletal Myoblasts Mol. Cell. Biol., July 1, 2000; 20(13): 4658 - 4665. [Abstract] [Full Text]

				C. Ruwhof and A. van der Laarse Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways Cardiovasc Res, July 1, 2000; 47(1): 23 - 37. [Abstract] [Full Text] [PDF]

				C. J. Auernhammer and S. Melmed Leukemia-Inhibitory Factor--Neuroimmune Modulator of Endocrine Function Endocr. Rev., June 1, 2000; 21(3): 313 - 345. [Abstract] [Full Text]

				A. Clerk and P. H. Sugden Small Guanine Nucleotide-Binding Proteins and Myocardial Hypertrophy Circ. Res., May 26, 2000; 86(10): 1019 - 1023. [Abstract] [Full Text] [PDF]

				W. Li, M. Han, and K.-L. Guan The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf Genes & Dev., April 15, 2000; 14(8): 895 - 900. [Abstract] [Full Text]

				J. Urano, A. P. Tabancay, W. Yang, and F. Tamanoi The Saccharomyces cerevisiae Rheb G-protein Is Involved in Regulating Canavanine Resistance and Arginine Uptake J. Biol. Chem., April 6, 2000; 275(15): 11198 - 11206. [Abstract] [Full Text] [PDF]

				M. A. Bogoyevitch Signalling via stress-activated mitogen-activated protein kinases in the cardiovascular system Cardiovasc Res, March 1, 2000; 45(4): 826 - 842. [Abstract] [Full Text] [PDF]

				W. Tian, G. R. Boss, and D. M. Cohen Ras signaling in the inner medullary cell response to urea and NaCl Am J Physiol Cell Physiol, February 1, 2000; 278(2): C372 - C380. [Abstract] [Full Text] [PDF]

				T. Zhu and P. E. Lobie Janus Kinase 2-dependent Activation of p38 Mitogen-activated Protein Kinase by Growth Hormone. RESULTANT TRANSCRIPTIONAL ACTIVATION OF ATF-2 AND CHOP, CYTOSKELETAL RE-ORGANIZATION AND MITOGENESIS J. Biol. Chem., January 21, 2000; 275(3): 2103 - 2114. [Abstract] [Full Text] [PDF]

				Y. Y. Wu and R. A. Bradshaw Activation of the Stat3 Signaling Pathway Is Required for Differentiation by Interleukin-6 in PC12-E2 Cells J. Biol. Chem., January 21, 2000; 275(3): 2147 - 2156. [Abstract] [Full Text] [PDF]

				J. Kotzka, D. Müller-Wieland, G. Roth, L. Kremer, M. Munck, S. Schürmann, B. Knebel, and W. Krone Sterol regulatory element binding proteins (SREBP)-1a and SREBP-2 are linked to the MAP-kinase cascade J. Lipid Res., January 1, 2000; 41(1): 99 - 108. [Abstract] [Full Text]

				T.-S. Jou, S.-M. Leung, L. M. Fung, W. G. Ruiz, W. J. Nelson, and G. Apodaca Selective Alterations in Biosynthetic and Endocytic Protein Traffic in Madin-Darby Canine Kidney Epithelial Cells Expressing Mutants of the Small GTPase Rac1 Mol. Biol. Cell, January 1, 2000; 11(1): 287 - 304. [Abstract] [Full Text]

				M. M. Muthalif, I. F. Benter, Z. Khandekar, L. Gaber, A. Estes, S. Malik, J.-H. Parmentier, V. Manne, and K. U. Malik Contribution of Ras GTPase/MAP Kinase and Cytochrome P450 Metabolites to Deoxycorticosterone-Salt-Induced Hypertension Hypertension, January 1, 2000; 35(1): 457 - 463. [Abstract] [Full Text] [PDF]

				K. K. Teng, D. K. Esposito, G. D. Schwartz, H. M. Lander, and B. L. Hempstead Activation of c-Ha-Ras by Nitric Oxide Modulates Survival Responsiveness in Neuronal PC12 Cells J. Biol. Chem., December 24, 1999; 274(52): 37315 - 37320. [Abstract] [Full Text] [PDF]

				M. Vo{beta}, P. A. O. Weernink, S. Haupenthal, U. Moller, R. H. Cool, B. Bauer, J. H. Camonis, K. H. Jakobs, and M. Schmidt Phospholipase D Stimulation by Receptor Tyrosine Kinases Mediated by Protein Kinase C and a Ras/Ral Signaling Cascade J. Biol. Chem., December 3, 1999; 274(49): 34691 - 34698. [Abstract] [Full Text] [PDF]

				S.-M. Leung, R. Rojas, C. Maples, C. Flynn, W. G. Ruiz, T.-S. Jou, and G. Apodaca Modulation of Endocytic Traffic in Polarized Madin-Darby Canine Kidney Cells by the Small GTPase RhoA Mol. Biol. Cell, December 1, 1999; 10(12): 4369 - 4384. [Abstract] [Full Text]

				J. M. Haugh, A. C. Huang, H. S. Wiley, A. Wells, and D. A. Lauffenburger Internalized Epidermal Growth Factor Receptors Participate in the Activation of p21ras in Fibroblasts J. Biol. Chem., November 26, 1999; 274(48): 34350 - 34360. [Abstract] [Full Text] [PDF]

				J. X. Zou, B. Wang, M. S. Kalo, A. H. Zisch, E. B. Pasquale, and E. Ruoslahti An Eph receptor regulates integrin activity through R-Ras PNAS, November 23, 1999; 96(24): 13813 - 13818. [Abstract] [Full Text] [PDF]

				I. E. Mazzoni, F. A. Said, R. Aloyz, F. D. Miller, and D. Kaplan Ras Regulates Sympathetic Neuron Survival by Suppressing the p53-Mediated Cell Death Pathway J. Neurosci., November 15, 1999; 19(22): 9716 - 9727. [Abstract] [Full Text] [PDF]

				R. E. Rhoads Signal Transduction Pathways That Regulate Eukaryotic Protein Synthesis J. Biol. Chem., October 22, 1999; 274(43): 30337 - 30340. [Full Text] [PDF]

				M. P. Sajan, M. L. Standaert, G. Bandyopadhyay, M. J. Quon, T. R. Burke Jr., and R. V. Farese Protein Kinase C-zeta and Phosphoinositide-dependent Protein Kinase-1 Are Required for Insulin-induced Activation of ERK in Rat Adipocytes J. Biol. Chem., October 22, 1999; 274(43): 30495 - 30500. [Abstract] [Full Text] [PDF]

				T. I. McLean and S. L. Bachenheimer Activation of cJUN N-Terminal Kinase by Herpes Simplex Virus Type 1 Enhances Viral Replication J. Virol., October 1, 1999; 73(10): 8415 - 8426. [Abstract] [Full Text] [PDF]

				J. S. Russell, F. F. Lang, T. Huet, M. Janicot, S. Chada, D. R. Wilson, and P. J. Tofilon Radiosensitization of Human Tumor Cell Lines Induced by the Adenovirus-mediated Expression of an Anti-Ras Single-Chain Antibody Fragment Cancer Res., October 1, 1999; 59(20): 5239 - 5244. [Abstract] [Full Text] [PDF]

				R. Yu, W. Lei, S. Mandlekar, M. J. Weber, C. J. Der, J. Wu, and A.-N. T. Kong Role of a Mitogen-activated Protein Kinase Pathway in the Induction of Phase II Detoxifying Enzymes by Chemicals J. Biol. Chem., September 24, 1999; 274(39): 27545 - 27552. [Abstract] [Full Text] [PDF]

				D. Rajesh, K. Schell, and A. K. Verma Ras Mutation, Irrespective of Cell Type and p53 Status, Determines a Cell's Destiny to Undergo Apoptosis by Okadaic Acid, an Inhibitor of Protein Phosphatase 1 and 2A Mol. Pharmacol., September 1, 1999; 56(3): 515 - 525. [Abstract] [Full Text]

				H. H. Lin, M. D. Zentner, H.-L. L. Ho, K.-J. Kim, and D. K. Ann The Gene Expression of the Amiloride-sensitive Epithelial Sodium Channel alpha -Subunit Is Regulated by Antagonistic Effects between Glucocorticoid Hormone and Ras Pathways in Salivary Epithelial Cells J. Biol. Chem., July 30, 1999; 274(31): 21544 - 21554. [Abstract] [Full Text] [PDF]

				K. Sawamoto, P. Winge, S. Koyama, Y. Hirota, C. Yamada, S. Miyao, S. Yoshikawa, M.-h. Jin, A. Kikuchi, and H. Okano The Drosophila Ral GTPase Regulates Developmental Cell Shape Changes through the Jun NH2-terminal Kinase Pathway J. Cell Biol., July 26, 1999; 146(2): 361 - 372. [Abstract] [Full Text] [PDF]

				A. Chiloeches, H. F. Paterson, R. Marais, A. Clerk, C. J. Marshall, and P. H. Sugden Regulation of Ras{middle dot}GTP Loading and Ras-Raf Association in Neonatal Rat Ventricular Myocytes by G Protein-coupled Receptor Agonists and Phorbol Ester. ACTIVATION OF THE EXTRACELLULAR SIGNAL-REGULATED KINASE CASCADE BY PHORBOL ESTER IS MEDIATED BY Ras J. Biol. Chem., July 9, 1999; 274(28): 19762 - 19770. [Abstract] [Full Text] [PDF]

				Y.-H. Wang and R. A. Maurer A Role for the Mitogen-Activated Protein Kinase in Mediating the Ability of Thyrotropin-Releasing Hormone to Stimulate the Prolactin Promoter Mol. Endocrinol., July 1, 1999; 13(7): 1094 - 1104. [Abstract] [Full Text]

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