Figure 3.

Signal transduction pathways demonstrate the different molecular consequences of ligand activation of IGF1R by IGF-1, including the activation of MAPK and PI3K/AKT cascades, which, in turn, induces expression of genes, such as VEGF, and ubiquitin-mediated IGF1R degradation. The activation of HIF-1 by mTOR in the PI3K/AKT cascade may result in the expression of IGFBPs and offer a feedback control on the IGF-1 activity. By binding IGF-1, IGFBPs can prevent proteolysis and extend the half-life of IGF-1, while reducing its bioavailability. Therefore, IGFBP proteases can regulate IGF half-life and play a critical role in modulating IGF availability at the cellular level.