Requirement of TGF-β receptor-dependent activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases (Sapks) for TGF-β up-regulation of the urokinase-type plasminogen activator receptor
✍ Scribed by Jianbo Yue; Baodong Sun; Guangming Liu; Kathleen M. Mulder
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 279 KB
- Volume
- 199
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
We have previously demonstrated that activation of the Ras/Mapk pathways is required for transforming growth factor β (TGF‐β) induction of TGF‐β~1~ expression. Here we examined the role of the Ras/Mapk pathways in TGF‐β induction of urokinase‐type plasminogen activator receptor (uPAR) expression in untransformed intestinal epithelial cells (IECs). TGF‐β activated the stress‐activated protein kinases (Sapk)/c‐Jun N‐terminal kinases (JNKs) within 5–10 min, an effect that preceeded TGF‐β induction of uPAR expression in these cells. TGF‐β induction of both JNK1 activity and JunD phosphorylation was blocked by expression of a dominant‐negative mutant of the type II TGF‐β receptor (DN TβRII), a dominant‐negative mutant of MKK4 (DN MKK4), or a dominant‐negative mutant of Ras (RasN17), or by the addition of the JNK inhibitor SP600125. TGF‐β also induced AP‐1 complex formation at the distal AP‐1 site (−184 to −178) of the uPAR promoter within 2 h of TGF‐β addition, consistent with the time‐dependent up‐regulation of uPAR expression. The primary components present in the TGF‐β‐stimulated AP‐1 complex bound to the uPAR promoter were Jun D and Fra‐2. Moreover, addition of SP600125, or expression of DN MKK4 or DN TβRII, blocked TGF‐β up‐regulation of uPAR in IECs. Accordingly, our results indicate that TGF‐β activates the Ras/MKK4/JNK1 signaling cascade, leading to induction of AP‐1 activity, which, in turn, up‐regulates uPAR expression. Our results also indicate that the type II TGF‐β receptor (RII) is required for TGF‐β activation of JNK1 and the resulting up‐regulation of uPAR expression. J. Cell. Physiol. 199: 284–292, 2004© 2003 Wiley‐Liss, Inc.