puc-header

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

45 Pages Posted: 18 May 2019 Sneak Peek Status: Review Complete

See all articles by Eugènia Almacellas

Eugènia Almacellas

University of Barcelona, Faculty of Pharmacy and Food Sciences, Departament de Bioquímica i Biologia Molecular; Bellvitge Biomedical Research Institute (IDIBELL) - Laboratory of Cancer Metabolism, ONCOBELL Program

Anna Manzano

Bellvitge Biomedical Research Institute (IDIBELL); University of Barcelona - Unitat de Bioquímica, Departament de Ciències Fisiològiques

Antonio Gentilella

University of Barcelona, Faculty of Pharmacy and Food Sciences, Departament de Bioquímica i Biologia Molecular; Bellvitge Biomedical Research Institute (IDIBELL) - Laboratory of Cancer Metabolism, ONCOBELL Program

Santiago Ambrosio

Bellvitge Biomedical Research Institute (IDIBELL); University of Barcelona - Unitat de Bioquímica, Departament de Ciències Fisiològiques

Caroline Mauvezin

Bellvitge Biomedical Research Institute (IDIBELL) - Laboratory of Cancer Metabolism, ONCOBELL Program

Albert Tauler

University of Barcelona, Faculty of Pharmacy and Food Sciences, Departament de Bioquímica i Biologia Molecular; Bellvitge Biomedical Research Institute (IDIBELL) - Laboratory of Cancer Metabolism, ONCOBELL Program

More...

Abstract

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.

Keywords: mTORC1, E2F1, PFKFB3, PFK1, lysosomes, glucose, glycolysis, Rag B GTPase, Ragulator

Suggested Citation

Almacellas, Eugènia and Manzano, Anna and Gentilella, Antonio and Ambrosio, Santiago and Mauvezin, Caroline and Tauler, Albert, Phosphofructokinases Axis Controls Glucose-Dependent mTORC1 Activation Driven by E2F1 Oncogene (May 16, 2019). ISCIENCE-D-19-00432. Available at SSRN: https://ssrn.com/abstract=3389377 or http://dx.doi.org/10.2139/ssrn.3389377
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Eugènia Almacellas

University of Barcelona, Faculty of Pharmacy and Food Sciences, Departament de Bioquímica i Biologia Molecular ( email )

Barcelona
Spain

Bellvitge Biomedical Research Institute (IDIBELL) - Laboratory of Cancer Metabolism, ONCOBELL Program ( email )

Catalunya
Spain

Anna Manzano

Bellvitge Biomedical Research Institute (IDIBELL) ( email )

08908 Hospitalet de LLobregat
Spain

University of Barcelona - Unitat de Bioquímica, Departament de Ciències Fisiològiques ( email )

Barcelona
Spain

Antonio Gentilella

University of Barcelona, Faculty of Pharmacy and Food Sciences, Departament de Bioquímica i Biologia Molecular ( email )

Barcelona
Spain

Bellvitge Biomedical Research Institute (IDIBELL) - Laboratory of Cancer Metabolism, ONCOBELL Program ( email )

Catalunya
Spain

Santiago Ambrosio

Bellvitge Biomedical Research Institute (IDIBELL) ( email )

08908 Hospitalet de LLobregat
Spain

University of Barcelona - Unitat de Bioquímica, Departament de Ciències Fisiològiques ( email )

Barcelona
Spain

Caroline Mauvezin

Bellvitge Biomedical Research Institute (IDIBELL) - Laboratory of Cancer Metabolism, ONCOBELL Program ( email )

Catalunya
Spain

Albert Tauler (Contact Author)

University of Barcelona, Faculty of Pharmacy and Food Sciences, Departament de Bioquímica i Biologia Molecular ( email )

Barcelona
Spain

Bellvitge Biomedical Research Institute (IDIBELL) - Laboratory of Cancer Metabolism, ONCOBELL Program ( email )

Catalunya
Spain

Click here to go to Cell.com

Go to Cell.com

Paper statistics

Abstract Views
58
PlumX Metrics
Downloads
6