This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suzuki, K. Articles by Leof, E. B. Search for Related Content PubMed PubMed Citation Articles by Suzuki, K. Articles by Leof, E. B.

Transforming Growth Factor ß Signaling via Ras in Mesenchymal Cells Requires p21-Activated Kinase 2 for Extracellular Signal-Regulated Kinase-Dependent Transcriptional Responses

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-ß–stimulated 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):3673–82]

This article has been cited by other articles:

				K. Matsuzaki, C. Kitano, M. Murata, G. Sekimoto, K. Yoshida, Y. Uemura, T. Seki, S. Taketani, J.-i. Fujisawa, and K. Okazaki Smad2 and Smad3 Phosphorylated at Both Linker and COOH-Terminal Regions Transmit Malignant TGF-{beta} Signal in Later Stages of Human Colorectal Cancer Cancer Res., July 1, 2009; 69(13): 5321 - 5330. [Abstract] [Full Text] [PDF]

				R. A. Rahimi, M. Andrianifahanana, M. C. Wilkes, M. Edens, T. J. Kottom, J. Blenis, and E. B. Leof Distinct Roles for Mammalian Target of Rapamycin Complexes in the Fibroblast Response to Transforming Growth Factor-{beta} Cancer Res., January 1, 2009; 69(1): 84 - 93. [Abstract] [Full Text] [PDF]

				M. V. Stevens, D. M. Broka, P. Parker, E. Rogowitz, R. R. Vaillancourt, and T. D. Camenisch MEKK3 Initiates Transforming Growth Factor {beta}2-Dependent Epithelial-to-Mesenchymal Transition During Endocardial Cushion Morphogenesis Circ. Res., December 5, 2008; 103(12): 1430 - 1440. [Abstract] [Full Text] [PDF]

				L. Xia, H. Wang, S. Munk, J. Kwan, H. J. Goldberg, I. G. Fantus, and C. I. Whiteside High glucose activates PKC-{zeta} and NADPH oxidase through autocrine TGF-{beta}1 signaling in mesangial cells Am J Physiol Renal Physiol, December 1, 2008; 295(6): F1705 - F1714. [Abstract] [Full Text] [PDF]

				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]