c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity

The Sma and Mad related (Smad) family proteins are critical mediators of th e transforming growth factor-beta (TCF-beta) superfamily signaling. After T GF-beta -mediated phosphorylation and association with Smad4, Smad2 moves t o the nucleus and activates expression of specific genes through cooperativ e interactions with DNA-binding proteins, including members of the winged-h elix family of transcription factors, forkhead activin signal transducer (F AST)-1 and FAST2. TCF-beta has also been described to activate other signal ing pathways, such as the c-Jun N-terminal Kinase (JNK) pathway. Here, we s how that activation of JNK cascade blocked the ability of Smad2 to mediate TGF-beta -dependent activation of the FAST proteins. This inhibitory activi ty is mediated through the transcriptional factor c-jun, which enhances the association of Smad2 with the nuclear transcriptional corepressor TG-inter acting factor (TGIF), thereby interfering with the assembly of Smad2 and th e coactivator p300 in response to TGF-P signaling. Interestingly, c-Jun dir ectly binds to the nuclear transcriptional corepressor TGIF and is required for TGIF-mediated repression of Smad2 transcriptional activity. These stud ies thus reveal a mechanism for suppression of Smad2 signaling pathway by J NK cascade through transcriptional repression.