Relevance of Autophagy Induction by Gastrointestinal Hormones: Focus on the Incretin-Based Drug Target and Glucagon

Kanasaki, Keizo; Kawakita, Emi; Koya, Daisuke

Indeed, DPP-4 is the molecule that interacts with the key integrin, integrin β1 (Figure 3) , which can form a heterodimer with at least 11 α-subunits. Integrin β1 has the biological function FIGURE 3 | DPP-4 may target integrin β1-mediated suppression of autophagy. On the cell membrane, DPP-4 displays an interaction with integrin β1. Integrin β1 is important for focal adhesion complexes. These integrin β1-mediated cell adhesion complexes potentially inhibit both anoikis and autophagy. Indeed, autophagy is an important biological mechanism for protecting cells from anoikis as well. Autophagy also targets and inhibits focal adhesion complexes. of a "hub integrin" and acts as a receptor for specific ECM components, revealed in kidney epithelial cells (Glynne et al., 2001) or in T cell lymphoma (Elias et al., 2014) . The loss of membrane-bound DPP-4 has been associated with suppression of the phosphorylation of integrin β1 S785, which plays a key role in the cellular adhesion of integrin β1 to the ECM (Sato et al., 2005) . We have shown that the DPP-4 inhibitor linagliptin suppressed the interaction between DPP-4 and integrin β1, subsequently inhibiting the endothelial to mesenchymal transition program (Shi et al., 2015; Kanasaki, 2016) , the fibrogenic programs associated with the inhibition of autophagy (Singh et al., 2015) . Interestingly, in addition to the biological importance of integrin β1 on the suppression of autophagy, the autophagy pathway targets integrin β1 during nutrient starvation (Vlahakis and Debnath, 2017) . Autophagy degrades focal adhesion proteins and promotes turnover of those molecules (Vlahakis and Debnath, 2017) . Additionally, integrin-mediated cell adhesion to the ECM has been shown to protect cells from anoikis, the apoptosis induced by the lack of correct cell/ECM attachment. Once integrin-mediated interaction with the ECM is lost, cells induce autophagy for survival (Figure 3) . Autophagy induction has been shown to promote the survival of epithelial cells and adjustments in the absence of cell-matrix contact, resulting in the anoikis resistance (Yang et al., 2013; Chen et al., 2017; Talukdar et al., 2018) (Figure 3) . After autophagy was inhibited by either RNA interference or harboring of oncogenes, cells lost their ability to combat anoikis (Figure 3) .