Transforming growth factor beta 1-induced extracellular signal-regulated kinase signaling pathway (TGF-β1/ERK pathway)

The Transforming growth factor beta 1 (TGF-β1)-induced extracellular signal-regulated kinase (ERK) signaling pathway is a prominent non-canonical (Smad-independent) signaling route that plays a pivotal role in fibroblast biology [Zhang, 2009, Cell Research; Derynck & Zhang, 2003, Nature]. Upon binding of TGF-β1 to its cognate receptors (TGFBR1 and TGFBR2), the pathway can trigger the Ras-Raf-MEK-ERK kinase cascade, often through the phosphorylation of the adaptor protein Shc or via direct interaction with Rho GTPases [Zhang, 2009, Cell Research; Gui et al., 2012, Int J Mol Sci]. In fibroblasts, this pathway is a primary driver of the transition into myofibroblasts, characterized by the expression of alpha-smooth muscle actin (α-SMA) and the excessive synthesis of extracellular matrix (ECM) components like collagen and fibronectin [Gui et al., 2012, Int J Mol Sci; Khalil et al., 2017, J Clin Invest]. This process is central to the pathogenesis of various fibrotic conditions, including idiopathic pulmonary fibrosis (IPF), systemic sclerosis, and cardiac fibrosis [Khalil et al., 2017, J Clin Invest]. Furthermore, the TGF-β1/ERK axis is implicated in the tumor microenvironment, where it promotes cancer-associated fibroblast (CAF) activation and epithelial-mesenchymal transition (EMT), facilitating tumor progression and metastasis [Derynck & Zhang, 2003, Nature]. Therapeutic targeting of this pathway involves small molecule inhibitors of TGF-β receptors (e.g., Galunisertib) or downstream MEK/ERK inhibitors (e.g., Trametinib), although systemic inhibition of TGF-β signaling is associated with significant safety concerns such as cardiovascular toxicity and impaired wound healing [Gui et al., 2012, Int J Mol Sci; FDA Label for Ofev].

Other names

TGF-beta1/MAPK signalingNon-canonical TGF-beta signalingTGF-beta1-ERK1/2 axisTGF-beta-induced Ras/MAPK pathway

Inhibition of TGF-beta receptor type 1 (ALK5) kinase activity, inhibition of MEK1/2 phosphorylation, or antagonism of TGF-beta ligand binding to prevent downstream ERK activation [Zhang, 2009, Cell Research; Gui et al., 2012, Int J Mol Sci].