Relation of the IGF/IGF1R system to autophagy in colitis and colorectal cancer

Figure 1 The IGF/IGF1R axis: schematic representation of the composition and function. Signaling of the IGF/IGF1R axis is mediated by IRS and Shc. PI3K-AKT activation is the predominant downstream event, but the Ras/MEK/ERK and JNK/MAPK pathways can also be activated. IGF: Insulin-like growth factor; IGF1R: Insulin-like growth factor receptor 1; IRS: Insulin receptor substrate; PI3K: Phosphatidylinositol-3-kinase; AKT: Serine/threonine kinase, named protein kinase B (PKB); mTOR: Mammalian target of rapamycin; Bad: Bcl-2-associated death promoter; Bcl2: B-cell lymphoma 2; Shc: Adaptor protein; Ras: GTPase protein; JNK: c-Jun N-terminal kinase; MEK: Mitogen-activated protein kinase kinase; ERK: Extracellular regulated kinase; MAPK: Mitogen-activated protein kinase; ELK: ETS domain-containing protein.

Figure 2 Controversial therapeutic effects of IGF1R inhibition. In case of IGF1R inhibition the simultaneously induced cell-protective autophagy could promote cell proliferation and suppress apoptosis, thus via autophagy antagonize its own original actions on cells. If IGF1R inhibition is combined with autophagy disruptive agents autophagy can be blocked, hence cancer cell proliferation will be suppressed and apoptosis enhanced. IGF1R: Insulin-like growth factor receptor 1.

Figure 3 Proposed model for the bi-directional IGF1R signaling-dependent modulation of the autophagic pathway. IGF1R targeting via suppression of the "canonical" PI3K/Akt/mTORC1 pathway stimulates the autophagy process. However, it can also result in a reduced formation of autophagosomal precursors at the plasma membrane. IGF1R depletion inhibits mTORC2, which reduces the activity of protein kinase C alpha and beta. This finally negatively impacts autophagosome precursor formation. IGF1R: Insulin-like growth factor receptor 1; PI3K: Phosphatidylinositol-3-kinase; AKT: Serine/threonine kinase, named protein kinase B (PKB); mTORC1/2: Mammalian target of rapamycin complex 1/2; PKC: Protein kinase C; ATG16L1: Autophagy-related protein 16-1.