Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Mol. Cell. Biol. 23 (23): 8878-8889

Copyright © 2003 by the American Society for Microbiology. All rights reserved.

Cell-Type-Specific Activation of PAK2 by Transforming Growth Factor ß Independent of Smad2 and Smad3

Mark C. Wilkes, Stephen J. Murphy, Nandor Garamszegi, and Edward B. Leof*

Department of Biochemistry and Molecular Biology, Thoracic Diseases Research Unit, and Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester Minnesota 55905

Received for publication 8 May 2003. Revision received 10 June 2003. Accepted for publication 21 August 2003.

Abstract: Transforming growth factor ß (TGF-ß) causes growth arrest in epithelial cells and proliferation and morphological transformation in fibroblasts. Despite the ability of TGF-ß to induce various cellular phenotypes, few discernible differences in TGF-ß signaling between cell types have been reported, with the only well-characterized pathway (the Smad cascade) seemingly under identical control. We determined that TGF-ß receptor signaling activates the STE20 homolog PAK2 in mammalian cells. PAK2 activation occurs in fibroblast but not epithelial cell cultures and is independent of Smad2 and/or Smad3. Furthermore, we show that TGF-ß-stimulated PAK2 activity is regulated by Rac1 and Cdc42 and dominant negative PAK2 or morpholino antisense oligonucleotides to PAK2 prevent the morphological alteration observed following TGF-ß addition. Thus, PAK2 represents a novel Smad-independent pathway that differentiates TGF-ß signaling in fibroblast (growth-stimulated) and epithelial cell (growth-inhibited) cultures.


* Corresponding author. Mailing address: Stabile 858, Mayo Clinic, Rochester, MN 55905. Phone: (507) 284-5717. Fax: (507) 284-4521. E-mail: leof.edward{at}mayo.edu.



THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Profibrotic TGF{beta} responses require the cooperative action of PDGF and ErbB receptor tyrosine kinases.
M. Andrianifahanana, M. C. Wilkes, S. K. Gupta, R. A. Rahimi, C. E. Repellin, M. Edens, J. Wittenberger, X. Yin, E. Maidl, J. Becker, et al. (2013)
FASEB J 27, 4444-4454
   Abstract »    Full Text »    PDF »
TGF{beta} receptor I transactivation mediates stretch-induced Pak1 activation and CTGF upregulation in mesangial cells.
G. Chen, X. Chen, A. Sukumar, B. Gao, J. Curley, H. W. Schnaper, A. J. Ingram, and J. C. Krepinsky (2013)
J. Cell Sci. 126, 3697-3712
   Abstract »    Full Text »    PDF »
Rbms3 functions in craniofacial development by posttranscriptionally modulating TGF-{beta} signaling.
C. S. Jayasena and M. E. Bronner (2012)
J. Cell Biol. 199, 453-466
   Abstract »    Full Text »    PDF »
p21-activated Kinase 2 (PAK2) Inhibits TGF-{beta} Signaling in Madin-Darby Canine Kidney (MDCK) Epithelial Cells by Interfering with the Receptor-Smad Interaction.
X. Yan, J. Zhang, Q. Sun, P. T. Tuazon, X. Wu, J. A. Traugh, and Y.-G. Chen (2012)
J. Biol. Chem. 287, 13705-13712
   Abstract »    Full Text »    PDF »
Non-Smad Transforming Growth Factor-{beta} Signaling Regulated by Focal Adhesion Kinase Binding the p85 Subunit of Phosphatidylinositol 3-Kinase.
M. Hong, M. C. Wilkes, S. G. Penheiter, S. K. Gupta, M. Edens, and E. B. Leof (2011)
J. Biol. Chem. 286, 17841-17850
   Abstract »    Full Text »    PDF »
Type II Transforming Growth Factor-{beta} Receptor Recycling Is Dependent upon the Clathrin Adaptor Protein Dab2.
S. G. Penheiter, R. Deep Singh, C. E. Repellin, M. C. Wilkes, M. Edens, P. H. Howe, R. E. Pagano, and E. B. Leof (2010)
Mol. Biol. Cell 21, 4009-4019
   Abstract »    Full Text »    PDF »
ERBB Receptor Activation Is Required for Profibrotic Responses to Transforming Growth Factor {beta}.
M. Andrianifahanana, M. C. Wilkes, C. E. Repellin, M. Edens, T. J. Kottom, R. A. Rahimi, and E. B. Leof (2010)
Cancer Res. 70, 7421-7430
   Abstract »    Full Text »    PDF »
Noncanonical TGF-{beta} pathways, mTORC1 and Abl, in renal interstitial fibrogenesis.
S. Wang, M. C. Wilkes, E. B. Leof, and R. Hirschberg (2010)
Am J Physiol Renal Physiol 298, F142-F149
   Abstract »    Full Text »    PDF »
Informatics approaches to understanding TGF{beta} pathway regulation.
P. Kahlem and S. J. Newfeld (2009)
Development 136, 3729-3740
   Abstract »    Full Text »    PDF »
Rac1 promotes TGF-{beta}-stimulated mesangial cell type I collagen expression through a PI3K/Akt-dependent mechanism.
S. C. Hubchak, E. E. Sparks, T. Hayashida, and H. W. Schnaper (2009)
Am J Physiol Renal Physiol 297, F1316-F1323
   Abstract »    Full Text »    PDF »
Distinct Roles for Mammalian Target of Rapamycin Complexes in the Fibroblast Response to Transforming Growth Factor-{beta}.
R. A. Rahimi, M. Andrianifahanana, M. C. Wilkes, M. Edens, T. J. Kottom, J. Blenis, and E. B. Leof (2009)
Cancer Res. 69, 84-93
   Abstract »    Full Text »    PDF »
BMP2 induction of actin cytoskeleton reorganization and cell migration requires PI3-kinase and Cdc42 activity.
C. Gamell, N. Osses, R. Bartrons, T. Ruckle, M. Camps, J. L. Rosa, and F. Ventura (2008)
J. Cell Sci. 121, 3960-3970
   Abstract »    Full Text »    PDF »
TGF{beta} mediates activation of transglutaminase 2 in response to oxidative stress that leads to protein aggregation.
D.-M. Shin, J.-H. Jeon, C.-W. Kim, S.-Y. Cho, H.-J. Lee, G.-Y. Jang, E. M. Jeong, D.-S. Lee, J.-H. Kang, G. Melino, et al. (2008)
FASEB J 22, 2498-2507
   Abstract »    Full Text »    PDF »
A Unique Element in the Cytoplasmic Tail of the Type II Transforming Growth Factor-beta Receptor Controls Basolateral Delivery.
S. J. Murphy, K. E. Shapira, Y. I. Henis, and E. B. Leof (2007)
Mol. Biol. Cell 18, 3788-3799
   Abstract »    Full Text »    PDF »
Arkadia Activates Smad3/Smad4-Dependent Transcription by Triggering Signal-Induced SnoN Degradation.
L. Levy, M. Howell, D. Das, S. Harkin, V. Episkopou, and C. S. Hill (2007)
Mol. Cell. Biol. 27, 6068-6083
   Abstract »    Full Text »    PDF »
Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-beta.
S. Xie, M. B. Sukkar, R. Issa, N. M. Khorasani, and K. F. Chung (2007)
Am J Physiol Lung Cell Mol Physiol 293, L245-L253
   Abstract »    Full Text »    PDF »
Transforming Growth Factor {beta} Signaling via Ras in Mesenchymal Cells Requires p21-Activated Kinase 2 for Extracellular Signal-Regulated Kinase-Dependent Transcriptional Responses.
K. Suzuki, M. C. Wilkes, N. Garamszegi, M. Edens, and E. B. Leof (2007)
Cancer Res. 67, 3673-3682
   Abstract »    Full Text »    PDF »
Potentiation of Smad-mediated transcriptional activation by the RNA-binding protein RBPMS.
Y. Sun, L. Ding, H. Zhang, J. Han, X. Yang, J. Yan, Y. Zhu, J. Li, H. Song, and Q. Ye (2006)
Nucleic Acids Res. 34, 6314-6326
   Abstract »    Full Text »    PDF »
TGFbeta Protein Processing and Activity through TCR Triggering of Primary CD8+ T Regulatory Cells.
A. Menoret, L. M. Myers, S.-J. Lee, R. S. Mittler, R. J. Rossi, and A. T. Vella (2006)
J. Immunol. 177, 6091-6097
   Abstract »    Full Text »    PDF »
Escaping from the TGF{beta} anti-proliferative control.
J. Seoane (2006)
Carcinogenesis 27, 2148-2156
   Abstract »    Full Text »    PDF »
HER2/Neu (ErbB2) Signaling to Rac1-Pak1 Is Temporally and Spatially Modulated by Transforming Growth Factor {beta}.
S. E. Wang, I. Shin, F. Y. Wu, D. B. Friedman, and C. L. Arteaga (2006)
Cancer Res. 66, 9591-9600
   Abstract »    Full Text »    PDF »
Transforming Growth Factor beta Activation of c-Abl Is Independent of Receptor Internalization and Regulated by Phosphatidylinositol 3-Kinase and PAK2 in Mesenchymal Cultures.
M. C. Wilkes and E. B. Leof (2006)
J. Biol. Chem. 281, 27846-27854
   Abstract »    Full Text »    PDF »
Galectin-3 regulates myofibroblast activation and hepatic fibrosis.
N. C. Henderson, A. C. Mackinnon, S. L. Farnworth, F. Poirier, F. P. Russo, J. P. Iredale, C. Haslett, K. J. Simpson, and T. Sethi (2006)
PNAS 103, 5060-5065
   Abstract »    Full Text »    PDF »
Requirement for the SnoN Oncoprotein in Transforming Growth Factor {beta}-Induced Oncogenic Transformation of Fibroblast Cells.
Q. Zhu, S. Pearson-White, and K. Luo (2005)
Mol. Cell. Biol. 25, 10731-10744
   Abstract »    Full Text »    PDF »
Transforming Growth Factor-{beta} Activation of Phosphatidylinositol 3-Kinase Is Independent of Smad2 and Smad3 and Regulates Fibroblast Responses via p21-Activated Kinase-2.
M. C. Wilkes, H. Mitchell, S. G. Penheiter, J. J. Dore, K. Suzuki, M. Edens, D. K. Sharma, R. E. Pagano, and E. B. Leof (2005)
Cancer Res. 65, 10431-10440
   Abstract »    Full Text »    PDF »
What Benjamin Babington, William Osler, Frederick Weber, and Henri Rendu did not know.
R. Hirschberg (2005)
Cardiovasc Res 68, 180-182
   Full Text »    PDF »
Smad4 Dependency Defines Two Classes of Transforming Growth Factor {beta} (TGF-{beta}) Target Genes and Distinguishes TGF-{beta}-Induced Epithelial-Mesenchymal Transition from Its Antiproliferative and Migratory Responses.
L. Levy and C. S. Hill (2005)
Mol. Cell. Biol. 25, 8108-8125
   Abstract »    Full Text »    PDF »
Non-Smad TGF-{beta} signals.
A. Moustakas and C.-H. Heldin (2005)
J. Cell Sci. 118, 3573-3584
   Abstract »    Full Text »    PDF »
High-Throughput Mapping of a Dynamic Signaling Network in Mammalian Cells.
M. Barrios-Rodiles, K. R. Brown, B. Ozdamar, R. Bose, Z. Liu, R. S. Donovan, F. Shinjo, Y. Liu, J. Dembowy, I. W. Taylor, et al. (2005)
Science 307, 1621-1625
   Abstract »    Full Text »    PDF »
Imatinib mesylate blocks a non-Smad TGF-{beta} pathway and reduces renal fibrogenesis in vivo.
S. Wang, M. C. Wilkes, E. B. Leof, and R. Hirschberg (2005)
FASEB J 19, 1-11
   Abstract »    Full Text »    PDF »
Analysis of Smad nucleocytoplasmic shuttling in living cells.
F. J. Nicolas, K. De Bosscher, B. Schmierer, and C. S. Hill (2004)
J. Cell Sci. 117, 4113-4125
   Abstract »    Full Text »    PDF »
Differential Trafficking of Transforming Growth Factor-{beta} Receptors and Ligand in Polarized Epithelial Cells.
S. J. Murphy, J. J. E. Dore, M. Edens, R. J. Coffey, J. A. Barnard, H. Mitchell, M. Wilkes, and E. B. Leof (2004)
Mol. Biol. Cell 15, 2853-2862
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882