Transforming growth factor-beta-induced p38 mitogen-activated protein kinase signaling cascade (TGF-β/p38 MAPK pathway)

The Transforming growth factor-beta (TGF-β)-induced p38 mitogen-activated protein kinase (MAPK) signaling cascade is a prominent non-canonical (Smad-independent) pathway that mediates diverse cellular responses to TGF-β ligands [2, 3]. Upon binding of TGF-β to its transmembrane serine/threonine kinase receptors (TβRI and TβRII), the receptor complex can activate p38 MAPK through both rapid, Smad-independent mechanisms involving adaptors like TRAF6 and the kinase TAK1, as well as delayed, Smad-dependent mechanisms involving GADD45β [3, 6]. This cascade is a critical regulator of the epithelial-mesenchymal transition (EMT), cell motility, and apoptosis, often functioning in parallel with the classical Smad2/3 pathway to drive complex biological outcomes [1, 2]. In pathological states, dysregulation of this signaling axis is strongly associated with cancer progression, metastasis, and the development of fibrotic diseases in organs such as the kidneys and lungs [3, 8]. Therapeutic intervention strategies focus on inhibiting the TGF-β receptors (e.g., galunisertib) or targeting the downstream p38 MAPK itself (e.g., losmapimod) to mitigate pro-invasive and pro-fibrotic effects [4, 8]. However, the pleiotropic nature of TGF-β signaling and the broad physiological roles of p38 MAPK present significant therapeutic challenges, including risks of cardiotoxicity and skin-related toxicities [8].

Other names

Non-canonical TGF-beta signalingSmad-independent TGF-beta signalingTGF-beta/p38 MAPK signaling pathwayTGF-beta-activated p38 MAPK cascade

The mechanism involves the pharmacological inhibition of upstream TGF-beta receptors (TβRI/ALK5) or downstream kinase components (TAK1, MKK3/6, p38 MAPK) to prevent the activation of transcription factors and effector proteins that drive EMT, fibrosis, and metastasis [3, 8].