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Fig. 4 | Journal of Experimental & Clinical Cancer Research

Fig. 4

From: Regulation of heterogeneous cancer-associated fibroblasts: the molecular pathology of activated signaling pathways

Fig. 4

A non-Smad TGF-β signaling pathway is involved in tissue fibrosis by promoting endothelial-mesenchymal transition (EndoMT). Following ligand-initiated activation of the Smad-independent TGF-β pathway, GSK-3β is phosphorylated by c-Abl and PKC-δ non-receptor kinases. Phosphorylation of GSK-3β at serine 9 (Ser9) causes its inhibition, which allows Snail1 to enter the nucleus. Nuclear accumulation of Snail1 leads to acquisition of the myofibroblast phenotype characterized by stimulation of α-SMA and type I collagen instead of VE-cadherin. The specific inhibition of c-Abl activity with imatinib allows GSK-3β to phosphorylate Snail1, which targets it for proteasomal degradation, thereby abolishing the acquisition of the myofibroblastic phenotype and the fibrotic response. Rottlerin and imatinib inhibit PKC-δ and c-Abl, respectively, which is why both agents abrogate EndoMT [116]. Note that ‘p’ indicates phosphorylation. Black arrows indicate induction or promotion, whereas blue arrows indicate inhibition

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