PAI-1 Regulates the Invasive Phenotype in Human Cutaneous Squamous Cell Carcinoma
Figure 6
A model for TGF-β1 induced PAI-1 transcription. Emerging studies suggest that transcriptional outputs from both SMAD2/3 as well as non-SMAD (e.g., EGFR-MEK/ERK) pathways are absolutely critical for TGF-β1-mediated PAI-1 induction. Activated Src kinases (e.g., c-Src), downstream of TGF-β1 receptor, function as an upstream regulator of EGFR transactivation (by Y845 phosphorylation). c-Src also modulates phosphorylation, and likely stimulates Rho/ROCK-dependent maintenance of SMAD2/3 transcriptional activity (by suppressing nuclear levels or activity of the SMAD2/3 phosphatase PPM1A). ERK1/2 (downstream of EGFR activation), or p38 kinases, may phosphorylate p53 and the bHLH-LZ upstream stimulatory factor proteins 1/2 (USF1/2) in response to TGF-β1. Indeed, SMAD2/3 appears to cooperate with p53 and USF family transcription factors for maximal TGF-β1-directed PAI-1 gene expression.
