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 Fan, S.
Right arrow Articles by Rosen, E. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fan, S.
Right arrow Articles by Rosen, E. M.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, August 2001, p. 4968-4984, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.4968-4984.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Multisubstrate Adapter Gab1 Regulates Hepatocyte Growth Factor (Scatter Factor)-c-Met Signaling for Cell Survival and DNA Repair

Saijun Fan,1 Yong Xian Ma,1 Min Gao,1 Ren-Qi Yuan,1 Qinghui Meng,1 Itzhak D. Goldberg,1 and Eliot M. Rosen1,2,*

Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040,1 and Department of Developmental and Molecular Biology, Hormone-Related Tumor Biology, and Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York 104612

Received 14 September 2000/Returned for modification 14 November 2000/Accepted 30 April 2001

Hepatocyte growth factor (scatter factor) (HGF/SF) is a pleiotrophic mediator of epithelial cell motility, morphogenesis, angiogenesis, and tumorigenesis. HGF/SF protects cells against DNA damage by a pathway from its receptor c-Met to phosphatidylinositol 3-kinase (PI3K) to c-Akt, resulting in enhanced DNA repair and decreased apoptosis. We now show that protection against the DNA-damaging agent adriamycin (ADR; topoisomerase IIalpha inhibitor) requires the Grb2-binding site of c-Met, and overexpression of the Grb2-associated binder Gab1 (a multisubstrate adapter required for epithelial morphogenesis) inhibits the ability of HGF/SF to protect MDCK epithelial cells against ADR. In contrast to Gab1 and its homolog Gab2, overexpression of c-Cb1, another multisubstrate adapter that associates with c-Met, did not affect protection. Gab1 blocked the ability of HGF/SF to cause the sustained activation of c-Akt and c-Akt signaling (FKHR phosphorylation). The Gab1 inhibition of sustained c-Akt activation and of cell protection did not require the Gab1 pleckstrin homology or SHP2 phosphatase-binding domain but did require the PI3K-binding domain. HGF/SF protection of parental MDCK cells was blocked by wortmannin, expression of PTEN, and dominant negative mutants of p85 (regulatory subunit of PI3K), Akt, and Pak1; the protection of cells overexpressing Gab1 was restored by wild-type or activated mutants of p85, Akt, and Pak1. These findings suggest that the adapter Gab1 may redirect c-Met signaling through PI3K away from a c-Akt/Pak1 cell survival pathway.

* Corresponding author. Mailing address: Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, 270-05 76th Ave., New Hyde Park, NY 11040. Phone: (718) 470-7386. Fax: (718) 470-9756. E-mail: erosen{at}lij.edu.

Molecular and Cellular Biology, August 2001, p. 4968-4984, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.4968-4984.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Fan, S., Meng, Q., Laterra, J. J., Rosen, E. M. (2009). Role of Src Signal Transduction Pathways in Scatter Factor-mediated Cellular Protection. J. Biol. Chem. 284: 7561-7577 [Abstract] [Full Text]  
  • Furuuchi, K., Berezov, A., Kumagai, T., Greene, M. I. (2007). Targeted Antireceptor Therapy with Monoclonal Antibodies Leads to the Formation of Inactivated Tetrameric Forms of ErbB Receptors. J. Immunol. 178: 1021-1029 [Abstract] [Full Text]  
  • Dance, M., Montagner, A., Yart, A., Masri, B., Audigier, Y., Perret, B., Salles, J.-P., Raynal, P. (2006). The Adaptor Protein Gab1 Couples the Stimulation of Vascular Endothelial Growth Factor Receptor-2 to the Activation of Phosphoinositide 3-Kinase. J. Biol. Chem. 281: 23285-23295 [Abstract] [Full Text]  
  • Shinomiya, N., Gao, C. F., Xie, Q., Gustafson, M., Waters, D. J., Zhang, Y.-W., Vande Woude, G. F. (2004). RNA Interference Reveals that Ligand-Independent Met Activity Is Required for Tumor Cell Signaling and Survival. Cancer Res. 64: 7962-7970 [Abstract] [Full Text]  
  • Kallin, A., Demoulin, J.-B., Nishida, K., Hirano, T., Ronnstrand, L., Heldin, C.-H. (2004). Gab1 Contributes to Cytoskeletal Reorganization and Chemotaxis in Response to Platelet-derived Growth Factor. J. Biol. Chem. 279: 17897-17904 [Abstract] [Full Text]  
  • Holgado-Madruga, M., Wong, A. J. (2004). Role of the Grb2-Associated Binder 1/SHP-2 Interaction in Cell Growth and Transformation. Cancer Res. 64: 2007-2015 [Abstract] [Full Text]  
  • Rasola, A., Anguissola, S., Ferrero, N., Gramaglia, D., Maffe, A., Maggiora, P., Comoglio, P. M., Di Renzo, M. F. (2004). Hepatocyte Growth Factor Sensitizes Human Ovarian Carcinoma Cell Lines to Paclitaxel and Cisplatin. Cancer Res. 64: 1744-1750 [Abstract] [Full Text]  
  • Sun, Y., Yuan, J., Liu, H., Shi, Z., Baker, K., Vuori, K., Wu, J., Feng, G.-S. (2004). Role of Gab1 in UV-Induced c-Jun NH2-Terminal Kinase Activation and Cell Apoptosis. Mol. Cell. Biol. 24: 1531-1539 [Abstract] [Full Text]  
  • Takeuchi, K., Ito, F. (2004). Suppression of Adriamycin-induced Apoptosis by Sustained Activation of the Phosphatidylinositol-3'-OH kinase-Akt Pathway. J. Biol. Chem. 279: 892-900 [Abstract] [Full Text]  
  • Dixit, M., Zhuang, D., Ceacareanu, B., Hassid, A. (2003). Treatment With Insulin Uncovers the Motogenic Capacity of Nitric Oxide in Aortic Smooth Muscle Cells: Dependence on Gab1 and Gab1-SHP2 Association. Circ. Res. 93 : e113-e123 [Abstract] [Full Text]  
  • Zhao, C., Ma, H., Bossy-Wetzel, E., Lipton, S. A., Zhang, Z., Feng, G.-S. (2003). GC-GAP, a Rho Family GTPase-activating Protein That Interacts with Signaling Adapters Gab1 and Gab2. J. Biol. Chem. 278: 34641-34653 [Abstract] [Full Text]  
  • Yu, C. F., Liu, Z.-X., Cantley, L. G. (2002). ERK Negatively Regulates the Epidermal Growth Factor-mediated Interaction of Gab1 and the Phosphatidylinositol 3-Kinase. J. Biol. Chem. 277: 19382-19388 [Abstract] [Full Text]  
  • Gao, M., Fan, S., Goldberg, I. D., Laterra, J., Kitsis, R. N., Rosen, E. M. (2001). Hepatocyte Growth Factor/Scatter Factor Blocks the Mitochondrial Pathway of Apoptosis Signaling in Breast Cancer Cells. J. Biol. Chem. 276: 47257-47265 [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»