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J. Biol. Chem., Vol. 282, Issue 14, 10405-10413, April 6, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/14/10405    most recent M611742200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend 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 Pannu, J. Articles by Trojanowska, M. Search for Related Content PubMed PubMed Citation Articles by Pannu, J. Articles by Trojanowska, M. Social Bookmarking                      What's this?

Transforming Growth Factor- Receptor Type I-dependent Fibrogenic Gene Program Is Mediated via Activation of Smad1 and ERK1/2 Pathways^*

Jaspreet Pannu, Sashidhar Nakerakanti, Edwin Smith, Peter ten Dijke, and Maria Trojanowska¹

From the Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425 and the Leiden University Medical Center, 2300 RC Leiden, The Netherlands

The transforming growth factor (TGF)-/Smad3 signaling pathway is considered a central mediator of pathological organ fibrosis; however, contribution of Smad2/3-independent TGF- signaling has not been fully explored. The present study utilized previously a described model of scleroderma (SSc) fibrosis based on forced expression of the TGF-RI (ALK5) (Pannu, J., Gardner, H., Shearstone, J. R., Smith, E., and Trojanowska, M. (2006) Arthritis Rheum. 54, 3011–3021). This study was aimed at determining the molecular mechanisms underlying the profibrotic program in this model. We demonstrate that the TGF-RI-dependent up-regulation of collagen and CCN2 (CTGF) does not involve Smad2/3 activation but is mediated by ALK1/Smad1 and ERK1/2 pathways. The following findings support this conclusion: (i) Smad2 and -3 were not phosphorylated in response to TGF-RI, (ii) a TGF-RI mutant defective in Smad2/3 activation, ALK5(3A), potently stimulated collagen production, (iii) elevation of TGF-RI triggered sustained association of ALK5 with ALK1 and high levels of Smad1 phosphorylation, (iv) blockade of Smad1 via small interfering RNA abrogated collagen and CCN2 up-regulation in this model, (v) elevated TGF-RI led to a prolonged activation of ERK1/2, (vi) the pharmacologic inhibitor of ERK1/2 inhibited Smad1 phosphorylation and abrogated profibrotic effects of elevated TGF-RI. Additional experiments demonstrated that a GC-rich response element located -6 to -16 (upstream of the transcription start site) in the CCN2 promoter mediated Smad1-dependent increased promoter activity in this model. This element was shown previously to mediate up-regulation of the CCN2 promoter in SSc fibroblasts. In conclusion, this study defines a novel ALK1/Smad1- and ERK1/2-dependent, Smad3-independent mode of TGF- signaling that may operate during chronic stages of fibrosis in SSc.

Received for publication, December 21, 2006

^* This work was supported by National Institutes of Health Grants AR-42334 and AR-44883 (to M. T.), the National Scleroderma Foundation (to J. P.), and the Dutch Cancer Society (to P. t. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed: CSB 912, 96 Jonathan Lucas St., Charleston, SC 29425. Tel.: 843-792-7921; Fax: 843-792-7121; E-mail: trojanme{at}musc.edu.

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