[HTML][HTML] TGF-β induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway

BA Hocevar, TL Brown, PH Howe - The EMBO journal, 1999 - embopress.org
The EMBO journal, 1999embopress.org
Transforming growth factor-β (TGF-β) exerts its effects on cell proliferation, differentiation
and migration in part through its modulation of extracellular matrix components, such as
fibronectin and plasminogen activator inhibitor-1 (PAI-1). Although the SMAD family of
proteins recently has been shown to be a key participant in TGF-β signaling, other signaling
pathways have also been shown to be activated by TGF-β. We report here that c-Jun N-
terminal kinase (JNK), a member of the MAP kinase family, is activated in response to TGF-β …
Transforming growth factor-β (TGF-β) exerts its effects on cell proliferation, differentiation and migration in part through its modulation of extracellular matrix components, such as fibronectin and plasminogen activator inhibitor-1 (PAI-1). Although the SMAD family of proteins recently has been shown to be a key participant in TGF-β signaling, other signaling pathways have also been shown to be activated by TGF-β. We report here that c-Jun N-terminal kinase (JNK), a member of the MAP kinase family, is activated in response to TGF-β in the human fibrosarcoma HT1080-derived cell line BAHgpt. Stable expression of dominant-negative forms of JNK1 and MKK4, an upstream activator of JNK, results in loss of TGF-β-stimulated fibronectin mRNA and protein induction, while having little effect on TGF-β-induced levels of PAI-1. The human fibronectin promoter contains three CRE elements, one of which has been shown to bind a c-Jun–ATF-2 heterodimer. Utilizing a GAL4 fusion trans-reporting system, we demonstrate a decrease in transactivating potential of GAL4–c-Jun and GAL4–ATF-2 in dominant-negative JNK1-and MKK4-expressing cells. Finally, we show that TGF-β-induced fibronectin synthesis is independent of Smad4. These results demonstrate that TGF-β-mediated fibronectin induction requires activation of JNK which in turn modulates the activity of c-Jun and ATF-2 in a Smad4independent manner.
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