The Complex Interplay of TGF-β and Notch Signaling in the Pathogenesis of Fibrosis

Figures

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  Figure 1. Cellular sources of myofibroblasts and fibrosis development. MSCs—mesenchymal stem cells; EMT—epithelia–mesenchymal transition; ECM—extracellular matrix. “Created with BioRender.com”.

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  Figure 2. TGF-β and Notch signaling pathways. TGF-β—transforming growth factor β; TβRI—TGF-β receptor 1; TβRII—TGF-β receptor 2; NECD—Notch extracellular domain; NICD—Notch intracellular domain; DLL—distal-less like; JAG—Jagged; DLL and JAG are Notch ligands; ADAM—ADAM metallopeptidase; ADAM and γ-secretase are needed to cleave Notch receptor and release NICD; CSL—NICD co-factor, its name is an abbreviation of the first letters of the members of its family from different animal groups: CBF-1/RBPJ (mammalian), Su(H) (drosophila), Lag-1 (nematoda); CoR—co-repressor; CoA—co-activator. See text for detail. “Created with BioRender.com”.

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  Figure 3. Brief summary of the interactions between TGF-β and Notch signaling pathways in the fibrosis of various organs. TGF-β and Notch act synergistically in the kidney, liver, and lung, leading to myofibroblast differentiation and fibrosis development. The TGF-β pathway induces fibrosis, but the role of Notch signaling in the process of cardiac fibrosis remains ambiguous and highly depends on cell context. Most studies demonstrate that Notch inhibits myofibroblast differentiation via antagonizing TGF-β pathway, but several studies point to possible synergistic interplay between these pathways and demonstrate profibrotic effect of Notch. Jag-1—Jagged-1. “Created with BioRender.com”.

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  Figure 4. The complex role of NICD-SMAD3 binding in TGF-β and Notch signaling transduction. Synergistic interaction: NICD-pSMAD3 complex moves to the nucleus, interacts with CSL, and enhances transcription of both TGF-β and Notch targets. NICD binding to pSMAD3 can increase the pSMAD3 half-life. Antagonistic interaction: NICD binds to pSMAD3 and sequestrates histone acetyltransferase P300 from it, blocking the transcription of TGF-β transcriptional targets. NICD binding to pSMAD3 can prevent its interaction with target gene promoters. NICD binding to pSMAD3 can promote degradation of the latter. CDK-cyclin-dependent kinase; NECD—Notch extracellular domain; NICD—Notch intracellular domain; SBE—SMAD binding element; CBE—CSL binding element. “Created with BioRender.com”.