Figure 9. A model for TGF-β1 stimulated maintenance of SMAD3 phosphorylation and PAI-1 induction via Src/FAK/Caveolin-1 signaling.

TGF-β1 stimulates caveolin-1^Y14 phosphorylation in a reactive oxygen species-FAK/c-Src dependent manner removing repressive influences on EGFR signaling (in red) leading to EGFR transactivation (also by c-Src), thereby, initiating signaling events leading to the MEK-ERK pathway activation necessary for PAI-1 induction. Src kinase phosphorylation of caveolin-1^Y14 also stimulates Rho-GTP loading and ROCK (an established downstream target of Rho) activation is necessary for PAI-1 induction. pCaveolin-1^Y14-Rho-ROCK mediated signaling leads to inhibition of PTEN-PPM1A interactions resulting in a reduction of nuclear PPM1A phosphatase (black pathway), thereby, maintaining the pSMAD2/3 levels (highlighted in blue) required for PAI-1 induction by TGF-β1 (see text). PAI-1 is elevated in atherosclerotic plaques frequently colocalizing with α-smooth muscle actin-expressing cells, presumably VSMCs (insert).