This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kimmelman, A. C.
Right arrow Articles by Chan, A. M.-L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kimmelman, A. C.
Right arrow Articles by Chan, A. M.-L.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, August 2002, p. 5946-5961, Vol. 22, No. 16
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.16.5946-5961.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

R-Ras3/M-Ras Induces Neuronal Differentiation of PC12 Cells through Cell-Type-Specific Activation of the Mitogen-Activated Protein Kinase Cascade

Alec C. Kimmelman, Nelson Nuñez Rodriguez, and Andrew M.-L. Chan*

The Derald H. Ruttenberg Cancer Center, The Mount Sinai School of Medicine, New York, New York 10029

Received 8 November 2001/ Returned for modification 15 March 2002/ Accepted 3 May 2002

R-Ras3/M-Ras is a novel member of the Ras subfamily of GTP-binding proteins which has a unique expression pattern highly restricted to the mammalian central nervous system. In situ hybridization using an R-Ras3 cRNA probe revealed high levels of R-Ras3 transcripts in the hippocampal region of the mouse brain as well as a pattern of expression in the cerebellum that was distinct from that of H-Ras. We found that R-Ras3 was activated by nerve growth factor (NGF) and basic fibroblast growth factor as well as by the guanine nucleotide exchange factor GRP but not by epidermal growth factor. Ectopic expression of either R-Ras3 or GRP in PC12 cells induced efficient neuronal differentiation. The ability of NGF as well as GRP to promote differentiation of PC12 cells was attenuated by an R-Ras3 dominant-negative mutant. Furthermore, the biological action of R-Ras3 in PC12 cells was dependent on the mitogen-activated protein kinase (MAPK). Interestingly, whereas R-Ras3 was unable to mediate efficient activation of MAPK activity in NIH 3T3 cells, it was able to do so in PC12 cells. This cell-type specificity is in stark contrast to that of H-Ras, which can stimulate the MAPK pathway in both cell types. Indeed, this pattern of MAPK activation could be explained by the fact that R-Ras3 was unable to activate c-Raf, while it bound and stimulated the neuronal Raf isoform, B-Raf, in PC12 cells. Thus, R-Ras3 is implicated in a novel pathway of neuronal differentiation by coupling specific trophic factors to the MAPK cascade through the activation of B-Raf.

* Corresponding author. Mailing address: Cancer Center, Mount Sinai School of Medicine, 1425 Madison Ave., Box #1130, New York, NY 10029. Phone: (212) 659-5490. Fax: (212) 849-2446. E-mail: andrew.chan{at}mssm.edu.

Molecular and Cellular Biology, August 2002, p. 5946-5961, Vol. 22, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.16.5946-5961.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Yokoyama, T., Takano, K., Yoshida, A., Katada, F., Sun, P., Takenawa, T., Andoh, T., Endo, T. (2007). DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras-ERK pathway, is required for myogenic differentiation. JCB 177: 781-793 [Abstract] [Full Text]  
  • Nunez Rodriguez, N., Lee, I. N. L., Banno, A., Qiao, H. F., Qiao, R. F., Yao, Z., Hoang, T., Kimmelman, A. C., Chan, A. M.-L. (2006). Characterization of R-ras3/m-ras null mice reveals a potential role in trophic factor signaling.. Mol. Cell. Biol. 26: 7145-7154 [Abstract] [Full Text]  
  • Sun, P., Watanabe, H., Takano, K., Yokoyama, T., Fujisawa, J.-i., Endo, T. (2006). Sustained activation of M-Ras induced by nerve growth factor is essential for neuronal differentiation of PC12 cells.. GENES CELLS 11: 1097-1113 [Abstract] [Full Text]  
  • Nishina, A., Kimura, H., Sekiguchi, A., Fukumoto, R.-h., Nakajima, S., Furukawa, S. (2006). Lysophosphatidylethanolamine in Grifola frondosa as a neurotrophic activator via activation of MAPK. J. Lipid Res. 47: 1434-1443 [Abstract] [Full Text]  
  • Grantcharova, E., Reusch, H. P., Beyermann, M., Rosenthal, W., Oksche, A. (2006). Endothelin A and Endothelin B Receptors Differ in Their Ability to Stimulate ERK1/2 Activation.. Exp. Biol. Med. 231: 757-760 [Abstract] [Full Text]  
  • Shi, G.-X., Han, J., Andres, D. A. (2005). Rin GTPase Couples Nerve Growth Factor Signaling to p38 and b-Raf/ERK Pathways to Promote Neuronal Differentiation. J. Biol. Chem. 280: 37599-37609 [Abstract] [Full Text]  
  • Shi, G.-X., Andres, D. A. (2005). Rit Contributes to Nerve Growth Factor-Induced Neuronal Differentiation via Activation of B-Raf-Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Cascades. Mol. Cell. Biol. 25: 830-846 [Abstract] [Full Text]  
  • Ehrhardt, A., David, M. D., Ehrhardt, G. R. A., Schrader, J. W. (2004). Distinct Mechanisms Determine the Patterns of Differential Activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by Receptors for Growth Factors or Antigen. Mol. Cell. Biol. 24: 6311-6323 [Abstract] [Full Text]  
  • Rodriguez-Viciana, P., Sabatier, C., McCormick, F. (2004). Signaling Specificity by Ras Family GTPases Is Determined by the Full Spectrum of Effectors They Regulate. Mol. Cell. Biol. 24: 4943-4954 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»