Fig. 1

Schematic representation of the gene TGFB(A) and protein TGF-β. A Gene structure of TGFB1, TGFB2, and TGFB3: The blue boxes represent the exons; the 5’- and 3’-untranslated region are marked in pink and green boxes, respectively. B Latent TGF-β synthesis and secretion: TGF-β precursor protein consists of a signal peptide, a LAP prodomain, and a mature TGF-β monomer sequence. With the removal of signal peptide, the precursor proteins are dimerized. After proteolytic cleavage, the mature TGF-β dimer remains associated with LAP prodomains and the SLC is formed. Then, SLC links with LTBP or LRRC and thus LLC is generated. The LLC is then secreted into extracellular matrix. C, D Once released from cells, the TGF-β dimer that is kept inactive by its binding with LTBP, which targets latent TGF-β into the ECM, or with an LRRC molecule that fixes latent TGF-β at the surface of cells. D, E integrin β, in association with integrin α, can bind with the RGD sequence in the latent TGF-β complex. Then, the increased tension at the interface leads to degradation of the LAP, and the physiological activation of latent TGF-β complexes result in the release of TGF-β ligands. These active TGF-β ligands bind to the TGFβRI/TGFβRII receptor complex at the cell surface, and the intracellular TGF-β signaling is initiated. LAP: latency-associated polypeptide or LAP. SLC: small latent complex; LTBP: latent TGF-β-binding protein; LLC: large latent complex; LRRC: leucine-rich repeat containing; RGD: arginine–glycine–aspartic acid motif. The short solid lines represent covalent bonds, while the short dashed lines are non-covalent bonds