Figure 1.
Epithelial and mesenchymal cell fibrogenic activation by TGF-β1: costimulation by other signaling inputs and opportunities for feed-forward activation. Latent TGF-β is activated by αv integrins. Active TGF-β binds to its receptors leading to activation of canonical Smad signaling and Smad-independent signaling pathways, including MAPK pathways and small GTPases such as RhoA. Inputs from other signaling pathways converge on these pathways to regulate the TGF-β response. These are activated by other growth factors, such as PDGF, which generally signal through RTKs and through MAPK, integrin-mediated mechanotransduction mediated by Rho family GTPases, and coactivators such as β-catenin. These signaling factors lead to expression of profibrotic genes such as those encoding α-SMA, ECM proteins, and secreted cytokines and growth factors, which further modify the fibrogenic effector cell response. The expression of transcription factors involved in epithelial or mesenchymal cell transition into an activated state is also induced. PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; RTK, receptor tyrosine kinase; MAPK, mitogen-activated protein kinase; (E)MT, (epithelial–) mesenchymal transition; Col, collagen; Fn, fibronectin; SMA, α-smooth muscle actin; ECM, extracellular matrix.