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Overview of transforming growth factor-beta signalling
Upregulated transforming growth factor-beta (TGFβ) signalling, driving mesenchymal cells to increase their production of ground substance and undergo a transition to a myofibroblast phenotype, is believed to play a pathogenic role in diverse fibrotic disorders, including benign prostatic hyperplasia, scleroderma, pulmonary fibrosis, glomerulosclerosis, tubulointerstial fibrosis, hepatic fibrosis, open angle glaucoma, Peyronie’s disease and the cardiac fibrosis associated with cardiac hypertrophy and heart failure.1–20 It should follow that safe, practical measures which downregulate such signalling may have potential for the prevention and control of these syndromes. Nutraceutical measures with this property have particular promise, as they might be employed for primary prevention. This issue is now of particular interest, as pulmonary fibrosis is emerging as a not-uncommon long-term complication of COVID-19.21 22
TGFβ signalling commences when this ligand binds to the type II TGFβ receptor (TβRII), inducing its association with the type I receptor (TβRI) to form a heterotrimer complex. The constitutive serine-threonine kinase activity of TβRII then phosphorylates TβRI, activating its dual-specificity kinase activity. Smad2 or Smad3 then bind to TβRI, which phosphorylates it on a serine. This phosphorylation enables Smad2/3 to complex with Smad4, forming a heterodimer which translates to the nucleus to serve as a transcription factor to promote expression of TGFβ-inducible genes.
However, the Smad2/3-Smad4 heterodimer quite frequently functions in concert with an AP-1 complex to mediate TGFβ-induced transcription.23–28 Activation of AP-1 reflects concurrent TGFβ-mediated activation of the mitogen-activated protein (MAP) kinases ERK, JNK and p38.29 30 Activation of the MAP kinase kinase kinase TAK1 is upstream from JNK and p38 MAP kinase in this signalling pathway. The E3 ubiquitin ligase TRAF6 is capable of binding to kinase-activated TβRI in the TGFβ receptor complex, and this induces the self-ubiquitination (K63) of TRAF6.31 32 The ubiquitinated TRAF6, in turn, interacts with TAK1 and …