Phosphofructokinases Axis Controls Glucose-Dependent mTORC1 Activation Driven by E2F1 Oncogene

Cancer cells rely on mTORC1 activity to coordinate mitogenic signaling with nutrients availability for growth. Based on the metabolic function of E2F1, we hypothesize that glucose catabolism driven by E2F1 could participate on mTORC1 activation. Here, we demonstrate that glucose potentiates E2F1-induced mTORC1 activation by promoting mTORC1 translocation to lysosomes, a process that occurs independently of AMPK activation. E2F1 regulates glucose metabolism by increasing anaerobic glycolysis and identified the key regulatory enzyme, PFKFB3, as E2F1 target gene responsible for mTORC1 activation. PFKFB3 and PFK1 were found associated to lysosomes and we demonstrated that modulation of PFKFB3 activity, either by subtract accessibility or gene expression, regulates the translocation of mTORC1 to lysosomes by direct interaction with Rag B and further mTORC1 activity. These results support a model where a glycolytic metabolon containing phosphofructokinases is present in the lysosome and acts as a sensor platform for glucose catabolism towards mTORC1 activity.