Figure 1
The relationship between the EGFR pathway, apoptosis and the DGKα -PDE4-cAMP-mTOR pathway was designed using the Ingenuity Pathway Analysis (IPA) software (https://www.ingenuity.com/).
EGFR stimulates intracellular signalling cascades, such as the RAS/RAF/ERK (MAPK) pathway—which induces BIM proteosomal degradation—and the PI3K/AKT/mTOR pathway. mTOR nucleates a rapamycin and nutrient -sensitive multiprotein complex called mTORC1 and a second growth-factor-sensitive but nutrient-insensitive mTOR-containing complex called mTORC2. Besides mTOR, mTORC1 contains Raptor, mLST8 (also known as GβL) and PRAS40 (proline-rich AKT substrate 40 kDa). mTORC2, like mTORC1, also includes the mLST8 protein, but instead of Raptor, mTORC2 contains the Rictor and mammalian stress-activated protein kinase [SAPK]-interacting (mSIN1) proteins. mTORC2 also contains Protor (protein observed with RICTOR). Ribosomal S6 kinase 70kDa (p70S6K) and eIF4E-binding protein 1 (4EBP1)—both regulators of mRNA translation—are the only extensively described mTORC1 substrates. Phosphorylation of the translational repressor 4EBP1 results in its dissociation from the eukaryotic initiation factor 4E (eIF4E), thereby allowing eIF4E to assemble with other translation initiation factors and initiate cap-dependent translation. mTORC2 directly phosphorylates and activates AKT. BIM activates BAK and BAX, causing activation and mitochondrial outer membrane permeabilization (MOMP). Anti-apoptotic BCL-2 proteins prevent MOMP by binding BIM and other BH3-only proteins as well as activated BAX or BAK. Following MOMP, release of various proteins from the mitochondrial intermembrane space promotes caspase activation and apoptosis. DGKα is a lipid kinase that phosphorylates the lipid diacylglycerol (DAG), transforming it into phosphatidic acid. Phosphatidic acid activates mTOR signalling via a unique pathway involving cAMP. The cAMP-degrading PDE4 enzymes also activate mTOR signalling. mTORC1 promotes survival through translational control of Mcl-1.
