| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Cell, Tumor, and Stem Cell Biology |
Department of Biochemistry and Molecular Biology, Thoracic Diseases Research Unit, and Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, Minnesota
Requests for reprints: Edward B. Leof, Stabile 8-58, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905. Phone: 507-284-5717; Fax: 507-284-4521; E-mail: leof.edward{at}mayo.edu.
Transforming growth factor ß (TGF-ß) signaling via Smad proteins occurs in various cell types. However, whereas the biological response to TGF-ß can be as distinct as growth promoting (i.e., mesenchymal cells) versus growth inhibiting (i.e., epithelial cells), few discernible differences in TGF-ß signaling have been reported. In the current study, we examined the role of Ras in the proliferative response to TGF-ß and how it might interface with Smad-dependent and Smad-independent TGF-ß signaling targets. TGF-ß stimulated Ras activity in a subset of mesenchymal, but not epithelial, cultures and was required for extracellular signal-regulated kinase (ERK)dependent transcriptional responses. Although dominant negative Ras had no effect on TGF-ß internalization or Smad-dependent signaling (i.e., phosphorylation, nuclear translocation, or SBE-luciferase activity), it did prevent the hyperphosphorylation of the Smad transcriptional corepressor TG-interacting factor (TGIF). This was not sufficient, however, to overcome the mitogenic response stimulated by TGF-ß, which was dependent on signals downstream of p21-activated kinase 2 (PAK2). Moreover, although the initial activation of Ras and PAK2 are distinctly regulated, TGF-ßstimulated PAK2 activity is required for Ras-dependent ERK phosphorylation and Elk-1 transcription. These findings show the requirement for crosstalk between two Smad-independent pathways in regulating TGF-ß proliferation and indicate that the mechanism(s) by which TGF-ß stimulates growth is not simply the opposite of its growth inhibitory actions. [Cancer Res 2007;67(8):367382]
This article has been cited by other articles:
![]() |
Y. Hu, X. Hu, L. Boumsell, and L. B. Ivashkiv IFN-{gamma} and STAT1 Arrest Monocyte Migration and Modulate RAC/CDC42 Pathways J. Immunol., June 15, 2008; 180(12): 8057 - 8065. [Abstract] [Full Text] [PDF] |
||||
![]() |
C.-L. Lin, J.-Y. Wang, J.-Y. Ko, K. Surendran, Y.-T. Huang, Y.-H. Kuo, and F.-S. Wang Superoxide Destabilization of {beta}-Catenin Augments Apoptosis of High-Glucose-Stressed Mesangial Cells Endocrinology, June 1, 2008; 149(6): 2934 - 2942. [Abstract] [Full Text] [PDF] |
||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |