Figure 2.

Schematic diagram showing the putative TGF-β signaling pathways involved in EndoMT. The diagram shows the numerous putative pathways that may participate in the EndoMT process and may be involved in the pathogenesis of human fibrotic disorders. One central pathway initiated following ligand-binding activation of the Smad-independent TGF-β pathway causes phosphorylation of GSK-3β mediated by PKC-δ and the cAbl non-receptor kinase. Phosphorylation of GSK-3β at serine 9 (ser9) causes its inhibition which then allows Snail1 to enter the nucleus. Nuclear accumulation of Snail1 results in marked stimulation of Snail1 expression which then leads to acquisition of the myofibroblast phenotype with stimulation of α-SMA. The inhibition of GSK-3β ser9 phosphorylation by specific inhibition of PKC-δ or c-Abl activity allows GSK-3β to phosphorylate Snail1 targeting it for proteosomal degradation and thus, effectively abolishes the acquisition of the myofibroblastic phenotype and the fibrotic response. Other pathways such as the ET-1, Wnt, hypoxia and cellular stress pathways may also participate although the molecular events have not been fully elucidated. Modified from Li and Jimenez [37].