Figure 2.

The canonical β-catenin/WNT pathway: “on” and “off” states. The hallmark of the canonical β-catenin/WNT pathway activation is the elevation of the cytoplasmic β-catenin protein level, the subsequent nuclear translocation of β-catenin and further activation of β-catenin specific gene transcription. The canonical β-catenin/WNT pathway can be either in “on-state” or in “off-state.” The pathway is in “on-state” in the presence of a WNT ligand that binds both Frizzled (FZD) and LRP5/6receptors. This leads to activation of the phosphoprotein Disheveled (DSH). DSH recruits the destruction complex (pGSK-3β + AXIN + APC) to the plasma membrane, where AXIN directly binds the cytoplasmic tail of LRP5/6. APC is the adenomatous polyposis coli and GSK-3β is the glycogen synthase kinase-3β. In “on-state,” pGSK-3β is inactivated which corresponds to the phosphorylated state (pGSK-3β). Activation of DSH leads to the inhibition of both phosphorylation and degradation of beta-catenin. Beta-catenin accumulates into the cytosol and then translocates to the nucleus to bind lymphoid-enhancing/T cell (LEF-TCF) co-transcription factors. This induces the WNT-response gene transcription. In the “off state,” in the absence of WNT ligand or in the presence of the active form of GSK-3β (i.e., the unphosphorylated form of GSK-3β), cytosolic β-catenin is phosphorylated by the active form of GSK-3β. Beta-catenin undergoes the destruction process into the proteasome. (A): at the pseudo-glandular stage of the pulmonary development, the canonical WNT/β-catenin pathway is in “on-state.” (B): at the saccular and alveolar states, and in normal infants, the canonical WNT/β-catenin pathway is in “off-state.” The pulmonary development is normal. (C): at the saccular and alveolar states, in preterm infants with BPD, the canonical WNT/β-catenin pathway is in “on-state” and the pulmonary development is dramatically impaired.