| First Author | Samarakoon R | Year | 2011 |
| Journal | PLoS One | Volume | 6 |
| Issue | 7 | Pages | e22896 |
| PubMed ID | 21829547 | Mgi Jnum | J:176254 |
| Mgi Id | MGI:5289760 | Doi | 10.1371/journal.pone.0022896 |
| Citation | Samarakoon R, et al. (2011) Redox-induced Src kinase and caveolin-1 signaling in TGF-beta1-initiated SMAD2/3 activation and PAI-1 expression. PLoS One 6(7):e22896 |
| abstractText | BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1), a major regulator of the plasmin-based pericellular proteolytic cascade, is significantly increased in human arterial plaques contributing to vessel fibrosis, arteriosclerosis and thrombosis, particularly in the context of elevated tissue TGF-beta1. Identification of molecular events underlying to PAI-1 induction in response to TGF-beta1 may yield novel targets for the therapy of cardiovascular disease. PRINCIPAL FINDINGS: Reactive oxygen species are generated within 5 minutes after addition of TGF-beta1 to quiescent vascular smooth muscle cells (VSMCs) resulting in pp60(c-src) activation and PAI-1 expression. TGF-beta1-stimulated Src kinase signaling sustained the duration (but not the initiation) of SMAD3 phosphorylation in VSMC by reducing the levels of PPM1A, a recently identified C-terminal SMAD2/3 phosphatase, thereby maintaining SMAD2/3 in an active state with retention of PAI-1 transcription. The markedly increased PPM1A levels in triple Src kinase (c-Src, Yes, Fyn)-null fibroblasts are consistent with reductions in both SMAD3 phosphorylation and PAI-1 expression in response to TGF-beta1 compared to wild-type cells. Activation of the Rho-ROCK pathway was mediated by Src kinases and required for PAI-1 induction in TGF-beta1-stimulated VSMCs. Inhibition of Rho-ROCK signaling blocked the TGF-beta1-mediated decrease in nuclear PPM1A content and effectively attenuated PAI-1 expression. TGF-beta1-induced PAI-1 expression was undetectable in caveolin-1-null cells, correlating with the reduced Rho-GTP loading and SMAD2/3 phosphorylation evident in TGF-beta1-treated caveolin-1-deficient cells relative to their wild-type counterparts. Src kinases, moreover, were critical upstream effectors of caveolin-1(Y14) phosphoryation and initiation of downstream signaling. CONCLUSIONS: TGF-beta1-initiated Src-dependent caveolin-1(Y14) phosphorylation is a critical event in Rho-ROCK-mediated suppression of nuclear PPM1A levels maintaining, thereby, SMAD2/3-dependent transcription of the PAI-1 gene. |
