835948.fig.003
Figure 3: Signaling pathways involved in EndoMT. The diagram shows the numerous putative pathways that may participate in the EndoMT process and may be involved in SSc pathogenesis. 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 c-Abl nonreceptor kinase. Phosphorylation of GSK-3β at serine 9 (ser9) causes its inhibition which then allows Snail-1 to enter the nucleus. Nuclear accumulation of Snail-1 results in marked stimulation of Snail-1 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 Snail-1 targeting it for proteosomal degradation and thus effectively abolishes the acquisition of the myofibroblastic phenotype and the fibrotic response. Other pathways such as those involving ET-1, Wnt, NOTCH, hypoxia, and cellular stress responses may also participate although the molecular events have not been fully elucidated. Modified from Piera-Velazquez and Jimenez [101].