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Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542 Laping NJ; Grygielko E; Mathur A; Butter S; Bomberger J; Tweed C; Martin W; Fornwald J; Lehr R; Harling J; Gaster L; Callahan JF; Olson BAMol Pharmacol 2002[Jul]; 62 (1): 58-64Transforming growth factor beta1 (TGF-beta1) is a potent fibrotic factor responsible for the synthesis of extracellular matrix. TGF-beta1 acts through the TGF-beta 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-beta 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-beta1-induced nuclear Smad3 localization. The p38 mitogen-activated protein kinase inhibitors SB-203580 and SB-202190 also inhibit phosphorylation of Smad3 by ALK5 with IC50 values of 6 and 3 microM, respectively. This suggests that these p38 MAPK inhibitors must be used at concentrations of less than 10 microM 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-beta1-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-beta1-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-beta1-induced collagen Ialpha1 (col Ialpha1). These data indicate that some matrix markers that are stimulated by TGF-beta1 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 Ialpha1).|Activin Receptors, Type I/metabolism[MESH]|Benzamides/*pharmacology[MESH]|Collagen Type I/genetics/metabolism[MESH]|Dioxoles/*pharmacology[MESH]|Enzyme Inhibitors/*pharmacology[MESH]|Extracellular Matrix/drug effects/*metabolism[MESH]|Fibronectins/metabolism[MESH]|Humans[MESH]|Imidazoles/pharmacology[MESH]|Mitogen-Activated Protein Kinases/antagonists & inhibitors[MESH]|Plasminogen Activator Inhibitor 1/genetics/metabolism[MESH]|Protein Serine-Threonine Kinases/*antagonists & inhibitors[MESH]|Pyridines/pharmacology[MESH]|RNA, Messenger/drug effects/metabolism[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Transforming Growth Factor beta/metabolism[MESH]|Thrombospondin 1/genetics/metabolism[MESH]|Transforming Growth Factor beta/*antagonists & inhibitors[MESH]|Transforming Growth Factor beta1[MESH]|Tumor Cells, Cultured[MESH]|p38 Mitogen-Activated Protein Kinases[MESH] |
