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

The Transforming growth factor beta (TGF-β) signaling pathway components comprise a group of ligands, transmembrane receptors, and intracellular signaling proteins that regulate essential cellular processes such as proliferation, differentiation, and apoptosis [18, 19]. Signaling is initiated when TGF-β ligands bind to the Transforming growth factor beta receptor type 2 (TGFBR2), which then recruits and phosphorylates the Transforming growth factor beta receptor type 1 (TGFBR1/ALK5) [15]. This activation triggers the phosphorylation of SMAD proteins (SMAD2 and SMAD3), which form complexes with SMAD4 and translocate to the nucleus to modulate the transcription of target genes [16]. In early-stage carcinogenesis, the pathway often functions as a tumor suppressor by inducing cell cycle arrest; however, in advanced stages, it promotes tumor progression by stimulating the epithelial-mesenchymal transition (EMT), enhancing metastasis, and suppressing the anti-tumor immune response [22, 23]. Beyond oncology, the pathway is a central driver of pathological fibrosis in organs such as the lungs, liver, and kidneys by promoting the activation of myofibroblasts and the deposition of extracellular matrix [24]. Therapeutic strategies targeting these components include small molecule kinase inhibitors of ALK5, neutralizing monoclonal antibodies against TGF-β isoforms, and ligand traps designed to sequester circulating cytokines [12, 13]. Clinical development of these agents faces challenges due to the pathway's pleiotropic nature, which can lead to adverse effects like cardiovascular toxicity and the development of benign or malignant skin lesions [9, 10].

Other names

TGF-beta signaling pathwayTGFB signaling pathwaySMAD signaling pathwayTransforming growth factor beta receptor signaling complex

Drugs targeting the TGF-β pathway primarily function through the competitive inhibition of the ATP-binding site of the Transforming growth factor beta receptor type 1 (ALK5) kinase domain [12], the neutralization of specific TGF-β isoforms (TGF-β1, -β2, and -β3) using monoclonal antibodies to prevent receptor binding [13], or the use of bifunctional fusion proteins and ligand traps that sequester TGF-β ligands away from their cognate receptors [14].