Title

TGF-Beta Induces Fibronectin Synthesis Through a c-Jun N-terminal Kinase-Dependent, Smad4-Independent Pathway

Document Type

Article

Publication Date

3-1-1999

Abstract

Transforming growth factor- (TGF-) 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-signaling, other signaling pathways have also been shown to be activated by TGF-. We report here that c-Jun N-terminal kinase (JNK), a member of the MAP kinase family, is activated in response to TGF- 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--stimulated fibronectin mRNA and protein induction, while having little effect on TGF--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--induced fibronectin synthesis is independent of Smad4. These results demonstrate that TGF--mediated fibronectin induction requires activation of JNK which in turn modulates the activity of c-Jun and ATF-2 in a Smad4-independent manner.

DOI

10.1093/emboj/18.5.1345