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. 2008 Apr 25;295(1):L143–L151. doi: 10.1152/ajplung.00289.2007

Fig. 7.

Fig. 7.

Model of EGF downregulation of tropoelastin expression in RFL-6 fibroblasts. Data demonstrate that EGF does not prevent TGF-β-induced nuclear accumulation of Smad2/3 but does stabilize the Smad corepressor TGIF via EGR/Mek/Erk-mediated phosphorylation of TGIF. Smad corepressor TGIF levels are normally very low because of the high turnover rate of TGIF protein. TGF-β signaling leads to transcription transactivation of a putative cytosolic factor X, which stabilizes tropoelastin mRNA by binding to tropoelastin mRNA and/or disrupting the interaction of tropoelastin mRNA and its degradation machinery. On EGF stimulation, activated Erk translocates to the nucleus, phosphorylates, and stabilizes Smad corepressor TGIF. Elevated levels of TGIF shut off transcription of factor X through competition with coactivator CBP/p300 for the activated Smad complex, leading to destabilization of tropoelastin mRNA and downregulation of tropoelastin expression. TβRI and TβRII, TGF-β type I and II receptors. *Indicates TGIF that has been phosphorylated by Erk.