FIGURE 2.

Canonical TGF-β signaling pathway and TGF-β signaling targeting therapies. After TGF-β mRNA translation (step I) and secretion, the large latent complex (LLC) composed of TGF-β, latency associated peptide (LAP), and latent TGF-β binding protein (LTBP) is deposited to the extracellular matrix (ECM). The interaction between LTBP and integrins increases TGF-β:LAP dissociation and TGF-β activation (step II). TGF-β binding to surface receptors (step III) is followed by TβRII-mediated TβRI transphosphorylation (step IV). The signaling is then transduced to cytosol by TβRI-induced phosphorylation of SMAD2 and 3 (step V), followed by their association with SMAD4, accumulation in the nucleus and regulation of target genes transcription. Anti-TGF-β therapies target critical steps in order to impair TGF-β signaling. Antisense oligonucleotides (ASOs) prevent the translation of TGF-β mRNA (step I). Anti-integrins prevent TGF-β activation (step II). Ligand traps avoid cytokine binding to its receptors (step III). TβRII and TβRI kinase inhibitors block type II-mediated type I receptor phosphorylation (step IV) and type I-mediated SMAD2 and 3 phosphorylation (step V), respectively.