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| Figure 1: Key mechanisms in PAI-1 expression control. TGF-β1-stimulated pp60c-src activity bifurcates into 2 signaling pathways. TGF-β1 stimulates caveolin-1Y14 phosphorylation removing repressive influences on EGFR signaling while inducing EGFRY845transactivation (also by pp60c-src) initiating downstream MAP kinase signaling to activate p53 and a USF1→USF2 switch as part of the required program of TGF-β1-dependent PAI-1 transcription. TGF-β1-initiated pp60c-src activation and caveolin-1Y14 phosphorylation also stimulate Rho-GTP loading and ROCK activation. pCaveolin-1Y14-Rho-ROCK-mediated signaling leads to inhibition of PTENPPM1A interactions resulting in a reduction of PPM1A activity maintaining, thereby, SMAD2/3 phosphorylation. |
