- TGF-β (Transforming Growth Factor-beta) signaling regulates diverse cellular processes including proliferation, differentiation, apoptosis, and extracellular matrix production. The pathway operates through both SMAD-dependent (canonical) and SMAD-independent (non-canonical) mechanisms.
- In canonical signaling, TGF-β ligands bind to type II receptors (TβRII), which then recruit and phosphorylate type I receptors (TβRI/ALK5). The activated type I receptors phosphorylate receptor-regulated SMADs (R-SMADs: SMAD2 and SMAD3). Phosphorylated R-SMADs form complexes with the common mediator SMAD4 and translocate to the nucleus, where they regulate gene expression in cooperation with other transcription factors.
- The pathway shows remarkable context-dependency in its effects. In normal epithelial cells, TGF-β typically inhibits proliferation and promotes apoptosis. However, in advanced cancers, it can promote epithelial-to-mesenchymal transition (EMT), invasion, and metastasis. This switch in TGF-β response, known as the “TGF-β paradox,” is a crucial aspect of cancer progression.
- Regulation occurs through multiple mechanisms including inhibitory SMADs (SMAD6 and SMAD7), receptor internalization, and various post-translational modifications. The pathway also integrates with other signaling networks including MAP kinase, PI3K/AKT, and Wnt pathways, allowing for complex cellular responses.
- Dysregulation of TGF-β signaling is implicated in numerous pathological conditions including fibrosis, autoimmune diseases, and cancer. This has led to the development of various therapeutic strategies targeting different components of the pathway, particularly for cancer and fibrotic diseases.
