Figure 2

Signaling pathways impinging on autophagy. The scheme illustrates the network of the principal kinases involved in the regulation of autophagy. Essentially, growth factors activate the mTORC1 complex (trough the inhibition of the TSC1/TSC2 complex), and this results in the inhibition of the ULK1(ATG1) complex and prevents the induction of autophagy. The abundance of aminoacids also results in down-regulation of this pathway through the inhibition of the Ras-Mek-Erk pathway, and by direct activation of mTOR through the RagA/B GTPases complex (not shown in the scheme). The lipid-kinase activity of PTEN prevents the activation of the Akt-mTOR pathway, and therefore removes the tonic inhibition of autophagy exerted by this pathway. This tonic inhibition can be also removed artificially by pharmacologic inhibition of mTOR with Rapamycin. Hypoxia and mitochondrial oxidative stress inhibit mTOR through the action of AMPk on the TSC1/TSC2 complex. Starvation (amino acid deprivation) activates the JNK pathway, which ends with the phosphorylation of bcl-2, thus allowing the formation of the autophagy interactome. Once activated, Vps34 produces PI3P, which acts as a platform for other autophagy proteins involved in autophagosomal membrane nucleation and elongation. A genotoxic stress activates p53 and other transcription factors (e.g., TFEB) that promote the synthesis of autophagy proteins (e.g., DRAM, UVRAG, cathepsin D). However, high levels of cytoplasmic p53 (localized in the endoplasmic reticulum) result in the inhibition of autophagosome formation.