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Molecular Pharmacology

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Research ArticleArticle

Inhibition of Transforming Growth Factor (TGF)-β1–Induced Extracellular Matrix with a Novel Inhibitor of the TGF-β Type I Receptor Kinase Activity: SB-431542

N. J. Laping, E. Grygielko, A. Mathur, S. Butter, J. Bomberger, C. Tweed, W. Martin, J. Fornwald, R. Lehr, J. Harling, L. Gaster, J. F. Callahan and B. A. Olson
Molecular Pharmacology July 2002, 62 (1) 58-64; DOI: https://doi.org/10.1124/mol.62.1.58
N. J. Laping
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E. Grygielko
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A. Mathur
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S. Butter
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J. Bomberger
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C. Tweed
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W. Martin
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J. Fornwald
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R. Lehr
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J. Harling
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L. Gaster
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J. F. Callahan
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B. A. Olson
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Abstract

Transforming growth factor β1 (TGF-β1) is a potent fibrotic factor responsible for the synthesis of extracellular matrix. TGF-β1 acts through the TGF-β type I and type II receptors to activate intracellular mediators, such as Smad proteins, the p38 mitogen-activated protein kinase (MAPK), and the extracellular signal-regulated kinase pathway. We expressed the kinase domain of the TGF-β type I receptor [activin receptor-like kinase (ALK)5] and the substrate, Smad3, and determined that SB-431542 is a selective inhibitor of Smad3 phosphorylation with an IC50 of 94 nM. It inhibited TGF-β1–induced nuclear Smad3 localization. The p38 mitogen-activated protein kinase inhibitors SB-203580 and SB-202190 also inhibit phosphorylation of Smad3 by ALK5 with IC50values of 6 and 3 μM, respectively. This suggests that these p38 MAPK inhibitors must be used at concentrations of less than 10 μM to selectively address p38 MAPK mechanisms. However, the p38 MAPK inhibitor SB-242235 did not inhibit ALK5. To evaluate the relative contribution of Smad signaling and p38 MAPK signaling in TGF-β1–induced matrix production, the effect of SB-431542 was compared with that of SB-242235 in renal epithelial carcinoma A498 cells. All compounds inhibited TGF-β1–induced fibronectin (FN) mRNA, indicating that FN synthesis is mediated in part via the p38 MAPK pathway. In contrast, SB-431542, but not the selective p38 MAPK inhibitor SB-242235, inhibited TGF-β1–induced collagen Iα1 (col Iα1). These data indicate that some matrix markers that are stimulated by TGF-β1 are mediated via the p38 MAPK pathway (i.e., FN), whereas others seem to be activated via ALK5 signaling independent of the p38 MAPK pathway (i.e., col Iα1).

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Molecular Pharmacology: 62 (1)
Molecular Pharmacology
Vol. 62, Issue 1
1 Jul 2002
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Research ArticleArticle

Inhibition of Transforming Growth Factor (TGF)-β1–Induced Extracellular Matrix with a Novel Inhibitor of the TGF-β Type I Receptor Kinase Activity: SB-431542

N. J. Laping, E. Grygielko, A. Mathur, S. Butter, J. Bomberger, C. Tweed, W. Martin, J. Fornwald, R. Lehr, J. Harling, L. Gaster, J. F. Callahan and B. A. Olson
Molecular Pharmacology July 1, 2002, 62 (1) 58-64; DOI: https://doi.org/10.1124/mol.62.1.58

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Research ArticleArticle

Inhibition of Transforming Growth Factor (TGF)-β1–Induced Extracellular Matrix with a Novel Inhibitor of the TGF-β Type I Receptor Kinase Activity: SB-431542

N. J. Laping, E. Grygielko, A. Mathur, S. Butter, J. Bomberger, C. Tweed, W. Martin, J. Fornwald, R. Lehr, J. Harling, L. Gaster, J. F. Callahan and B. A. Olson
Molecular Pharmacology July 1, 2002, 62 (1) 58-64; DOI: https://doi.org/10.1124/mol.62.1.58
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