PTEN dephosphorylates AKT to prevent the expression of GLUT1 on plasmamembrane and to limit glucose consumption in cancer cells
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Suratchanee Phadngam1,*, Andrea Castiglioni1,*, Alessandra Ferraresi1, Federica Morani1, Carlo Follo1, Ciro Isidoro1
1Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, 28100 - Novara, Italy
*These authors have contributed equally to this work and each should be regarded as first author
Ciro Isidoro, email: [email protected]
Keywords: glucose, warburg effect, AKT, PTEN, cancer
Received: July 22, 2016 Accepted: October 22, 2016 Published: November 04, 2016
GLUT1 is the facilitative transporter playing the major role in the internalization of glucose. Basally, GLUT1 resides on vesicles located in a para-golgian area, and is translocated onto the plasmamembrane upon activation of the PI3KC1-AKT pathway. In proliferating cancer cells, which demand a high quantity of glucose for their metabolism, GLUT1 is permanently expressed on the plasmamembrane. This is associated with the abnormal activation of the PI3KC1-AKT pathway, consequent to the mutational activation of PI3KC1 and/or the loss of PTEN. The latter, in fact, could antagonize the phosphorylation of AKT by limiting the availability of Phosphatidylinositol (3,4,5)-trisphosphate. Here, we asked whether PTEN could control the plasmamembrane expression of GLUT1 also through its protein-phosphatase activity on AKT. Experiments of co-immunoprecipitation and in vitro de-phosphorylation assay with homogenates of cells transgenically expressing the wild type or knocked-down mutants (lipid-phosphatase, protein-phosphatase, or both) isoforms demonstrated that indeed PTEN physically interacts with AKT and drives its dephosphorylation, and so limiting the expression of GLUT1 at the plasmamembrane. We also show that growth factors limit the ability of PTEN to dephosphorylate AKT. Our data emphasize the fact that PTEN acts in two distinct steps of the PI3k/AKT pathway to control the expression of GLUT1 at the plasmamembrane and, further, add AKT to the list of the protein substrates of PTEN.
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