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

The Transforming growth factor beta (TGF-β) signaling pathway is a fundamental regulator of cellular homeostasis, controlling processes such as cell proliferation, differentiation, apoptosis, and the production of the extracellular matrix [1, 2]. Signaling is initiated when TGF-β ligands bind to a heteromeric complex of type I and type II serine/threonine kinase receptors, leading to the phosphorylation of R-SMAD proteins (SMAD2/3) which then translocate to the nucleus to modulate gene transcription [1, 3]. In early-stage carcinogenesis, the pathway typically functions as a tumor suppressor by inducing cell cycle arrest; however, in advanced stages, it promotes tumor progression by driving epithelial-mesenchymal transition (EMT), metastasis, and creating an immunosuppressive tumor microenvironment [2, 5]. Beyond oncology, chronic activation of TGF-β signaling is a hallmark of fibrotic diseases affecting the lungs, liver, and kidneys, where it stimulates excessive collagen deposition [3]. Therapeutic interventions targeting this pathway include small molecule inhibitors of the TGF-β receptor I (ALK5) kinase, such as galunisertib, and monoclonal antibodies like fresolimumab that neutralize the ligands [4]. Despite its therapeutic potential, drug development has been hindered by significant safety concerns, most notably cardiotoxicity involving heart valve remodeling and the development of benign or malignant skin lesions [2, 4]. The complexity of the pathway, including its dual role as both a suppressor and promoter of disease, necessitates careful patient selection and the use of predictive biomarkers like SMAD phosphorylation levels [2, 5].

Other names

TGF-beta signalingTGFB pathwaySMAD signaling pathwayTGF-beta/SMAD pathway

Inhibition of TGF-beta receptor type 1 (ALK5) kinase activity, neutralization of TGF-beta ligands (TGF-beta 1, 2, and 3), and blockade of ligand-receptor interactions using decoy receptors or bifunctional fusion proteins [2, 4].