Transforming growth factor beta signaling pathway (TGF-β pathway) (TGF-β pathway)

The Transforming growth factor beta (TGF-β) signaling pathway is a critical regulator of diverse cellular processes, including cell growth, differentiation, apoptosis, and development (UniProt P01137). The pathway is initiated by the binding of TGF-β ligands (TGF-β1, 2, and 3) to a heteromeric complex of type I and type II serine/threonine kinase receptors, which subsequently phosphorylate SMAD proteins to regulate gene expression (PubMed: 28115516). In healthy tissues, TGF-β acts as a potent tumor suppressor by inducing cell cycle arrest; however, in advanced cancers, it often promotes tumor progression, metastasis, and immune evasion through the induction of epithelial-mesenchymal transition (EMT) (PubMed: 29133770). Beyond oncology, dysregulation of this pathway is a primary driver of organ fibrosis in the liver, lungs, and kidneys, as well as various cardiovascular pathologies (NIH: NCATS). Therapeutic strategies targeting this pathway include neutralizing monoclonal antibodies, small molecule kinase inhibitors, and bifunctional fusion proteins like bintrafusp alfa, which simultaneously targets TGF-β and PD-L1 (PubMed: 30643283). Despite its therapeutic potential, systemic inhibition of TGF-β faces challenges due to its pleiotropic nature, leading to concerns regarding cardiotoxicity and the development of secondary skin lesions (PubMed: 23633440).

Other names

TGF-beta signalingTGFB pathwayTGF-beta/Smad signaling pathwayTransforming growth factor beta receptor pathway

Inhibition of TGF-beta ligands via neutralizing antibodies or ligand traps, and inhibition of TGF-beta receptor type I (ALK5) kinase activity using small molecule inhibitors to block downstream SMAD phosphorylation and gene transcription.