TGFbeta

Transforming growth factor beta (TGF-β) is a cytokine that regulates a wide range of cellular processes, including growth, differentiation, and immune function. In humans there are three main isoforms—TGF-β1, TGF-β2, and TGF-β3—encoded by TGFB1, TGFB2, and TGFB3 genes. TGF-β is synthesized as part of a latent complex with latency-associated peptide (LAP) and latent TGF-β binding protein (LTBP); activation of the latent complex is required to enable signaling.

Signaling occurs through a serine/threonine kinase receptor system consisting of TGF-β type II receptor (TGFBR2) and type I receptor (TGFBR1/ALK5). Ligand binding triggers phosphorylation of SMAD2 and SMAD3, which pair with SMAD4 and translocate to the nucleus to regulate target gene expression (the canonical pathway). Noncanonical pathways include MAPK, Rho-like GTPases, and PI3K/AKT, contributing to diverse cellular outcomes.

TGF-β has pleiotropic roles, including control of cell proliferation and differentiation, regulation of extracellular matrix production, wound healing, and angiogenesis. It also modulates immune responses, generally inhibiting T cell activation and promoting regulatory T cells, with context-dependent effects on other T cell subsets and B cells.

Dysregulation of TGF-β signaling is implicated in several diseases. In cancer, TGF-β can act as a tumor suppressor in early stages but promote progression and metastasis later via epithelial-to-mesenchymal transition and immunosuppression. In fibrosis, chronic TGF-β signaling drives myofibroblast activation and excessive extracellular matrix deposition.

Therapeutic strategies aim to dampen TGF-β signaling in fibrotic diseases and cancer; examples include neutralizing antibodies such as fresolimumab and receptor kinase inhibitors such as galunisertib (ALK5 inhibitor). Measurement of TGF-β levels or activity is used as a biomarker in research settings.