TGF-β signaling

Transforming growth factor β (TGF-β) signaling is initiated when TGF-β ligands — including TGF-β1, TGF-β2, and TGF-β3 — bind to heteromeric serine/threonine kinase receptor complexes (TβRII/TβRI) that phosphorylate receptor-regulated SMADs (R-SMADs 2 and 3), which then partner with SMAD4 and translocate to the nucleus to modulate target gene expression. Beyond this canonical SMAD pathway, non-canonical branches engage MAPK, Rho-GTPase, and PI3K effectors. TGF-β is a contextually pleiotropic cytokine with anti-proliferative, immunomodulatory, pro-fibrotic, and pro-apoptotic functions; in the ageing context, elevated TGF-β1 is a component of the aged systemic milieu and has been implicated in suppressing neural progenitor activity and muscle stem cell function, as well as in driving fibrosis across multiple organs, making pathway antagonism an area of active therapeutic exploration.