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 Yang, C.
Right arrow Articles by Kazanietz, M. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, C.
Right arrow Articles by Kazanietz, M. G.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, February 2006, p. 831-842, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.831-842.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Essential Role for Rac in Heregulin ß1 Mitogenic Signaling: a Mechanism That Involves Epidermal Growth Factor Receptor and Is Independent of ErbB4

Chengfeng Yang,1 Ying Liu,1 Mark A. Lemmon,2 and Marcelo G. Kazanietz1*

Department of Pharmacology,1 Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-61602

Received 8 August 2005/ Returned for modification 1 September 2005/ Accepted 7 November 2005

Heregulins are a family of ligands for the ErbB3/ErbB4 receptors that play important roles in breast cancer cell proliferation and tumorigenesis. Limited information is available on the contribution of Rho GTPases to heregulin-mediated signaling. In breast cancer cells, heregulin ß1 (HRG) causes a strong activation of Rac; however, it does so with striking differences in kinetics compared to epidermal growth factor, which signals through ErbB1 (epidermal growth factor receptor [EGFR]). Using specific ErbB receptor inhibitors and depletion of receptors by RNA interference (RNAi), we established that, surprisingly, activation of Rac by HRG is mediated not only by ErbB3 and ErbB2 but also by transactivation of EGFR, and it is independent of ErbB4. Similar receptor requirements are observed for HRG-induced actin cytoskeleton reorganization and mitogenic activity via extracellular signal-regulated kinase (ERK). HRG-induced Rac activation was phosphatidylinositol 3-kinase dependent and Src independent. Furthermore, inactivation of Rac by expression of the Rac GTPase-activating protein ß2-chimerin inhibited HRG-induced ERK activation, mitogenicity, and migration in breast cancer cells. HRG mitogenic activity was also impaired by depletion of Rac1 using RNAi. Our studies established that Rac is a critical mediator of HRG mitogenic signaling in breast cancer cells and highlight additional levels of complexity for ErbB receptor coupling to downstream effectors that control aberrant proliferation and transformation.

* Corresponding author. Mailing address: Department of Pharmacology, University of Pennsylvania School of Medicine, 816 Biomedical Research Building II/III, 421 Curie Blvd., Philadelphia, PA 19104-6160. Phone: (215) 898-0253. Fax: (215) 573-9004. E-mail: marcelo{at}spirit.gcrc.upenn.edu.

Molecular and Cellular Biology, February 2006, p. 831-842, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.831-842.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dokmanovic, M., Hirsch, D. S., Shen, Y., Wu, W. J. (2009). Rac1 contributes to trastuzumab resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer. Molecular Cancer Therapeutics 8: 1557-1569 [Abstract] [Full Text]  
  • Siliceo, M., Merida, I. (2009). T Cell Receptor-dependent Tyrosine Phosphorylation of {beta}2-Chimaerin Modulates Its Rac-GAP Function in T Cells. J. Biol. Chem. 284: 11354-11363 [Abstract] [Full Text]  
  • Boguslavsky, S., Grosheva, I., Landau, E., Shtutman, M., Cohen, M., Arnold, K., Feinstein, E., Geiger, B., Bershadsky, A. (2007). p120 catenin regulates lamellipodial dynamics and cell adhesion in cooperation with cortactin. Proc. Natl. Acad. Sci. USA 104: 10882-10887 [Abstract] [Full Text]  
  • Ostrander, J. H., Daniel, A. R., Lofgren, K., Kleer, C. G., Lange, C. A. (2007). Breast Tumor Kinase (Protein Tyrosine Kinase 6) Regulates Heregulin-Induced Activation of ERK5 and p38 MAP Kinases in Breast Cancer Cells. Cancer Res. 67: 4199-4209 [Abstract] [Full Text]  
  • Bruinsma, S. P., Cagan, R. L., Baranski, T. J. (2007). Chimaerin and Rac regulate cell number, adherens junctions, and ERK MAP kinase signaling in the Drosophila eye. Proc. Natl. Acad. Sci. USA 104: 7098-7103 [Abstract] [Full Text]  
  • Wang, S. E., Shin, I., Wu, F. Y., Friedman, D. B., Arteaga, C. L. (2006). HER2/Neu (ErbB2) Signaling to Rac1-Pak1 Is Temporally and Spatially Modulated by Transforming Growth Factor {beta}. Cancer Res. 66: 9591-9600 [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»