Kinome Screen Identifies PFKFB3 and Glucose Metabolism as Important Regulators of the Insulin/Insulin-like Growth Factor (IGF)-1 Signaling Pathway

Trefely, Sophie; Khoo, Poh Sim; Krycer, James R.; Chaudhuri, Rima; Fazakerley, Daniel J.; Parker, Benjamin L.; Sultani, Ghazal; Lee, James; Stéphan, Jean-Philippe; Torres, Eric; Jung, Kenneth; Kuijl, Coenraad; James, David E.; Junutula, Jagath R.; Stöckli, Jacqueline

doi:10.1074/jbc.m115.658815

Cited by 60 publications

(40 citation statements)

References 103 publications

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“…Thus, we report that Akt activation is necessary for TIGAR modulation in the experimental conditions analysed. These results point out that HeLa cells lacking PFKFB3 trigger the mTORC2‐Akt‐mTORC1 prosurvival axis in an attempt to rescue glycolysis, since Akt has been widely described to activate GLUT1, Hexokinase, PFK‐1 and PFKFB3 , and be essential for tumour growth . On the contrary, Akt inhibition has been proven to decrease early metabolites in glycolysis and the pentose phosphate pathway , which is consistent with the inhibition of TIGAR that we have observed with Akti‐1/2.…”

Section: Discussionsupporting

confidence: 88%

“…1), and thus we wondered which signalling pathway could be orchestrating it. The mTORC2-Akt-mTORC1 axis has been described to control PFKFB3 levels [34,35] and, moreover, this pathway has been found activated in cancer cells under glucose deprivation conditions and oxidants exposure [36,37]. As we have shown, TIGAR limits ROS production after PFKFB3 inhibition (Fig.…”

Section: Akt Signalling Pathway Drives Tigar Induction In Response Tomentioning

confidence: 55%

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Akt mediates TIGAR induction in HeLa cells following PFKFB3 inhibition

et al. 2016

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Neoplastic cells metabolize higher amounts of glucose relative to normal cells in order to cover increased energetic and anabolic needs. Inhibition of the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) diminishes cancer cell proliferation and tumour growth in animals. In this work, we investigate the crosstalk between PFKFB3 and TIGAR (TP53-Induced Glycolysis and Apoptosis Regulator), a protein known to protect cells from oxidative stress. Our results show consistent TIGAR induction in HeLa cells in response to PFKFB3 knockdown. Upon PFKFB3 silencing, cells undergo oxidative stress and trigger Akt phosphorylation. This leads to induction of a TIGAR-mediated prosurvival pathway that reduces both oxidative stress and cell death. As TIGAR is known to have a role in DNA repair, it could serve as a potential target for the development of effective antineoplastic therapies.

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Section: Discussionsupporting

confidence: 88%

Section: Akt Signalling Pathway Drives Tigar Induction In Response Tomentioning

confidence: 55%

Akt mediates TIGAR induction in HeLa cells following PFKFB3 inhibition

et al. 2016

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“…4). Interestingly, PFKFB3 was recently suggested to participate in a positive feed- back loop that causes hyperphosphorylation of Akt and increases glucose transporter 4 translocation (75). We show that Akt is hyperphosphorylated and that glucose transporter 4 abundance is elevated in diabetic CPCs, which may be caused by PFKFB3 or elevated glycolytic rates in general.…”

Section: Discussionmentioning

confidence: 70%

Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells

Salabei

Lorkiewicz

Mehra

et al. 2016

Journal of Biological Chemistry

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Type 2 diabetes is associated with increased mortality and progression to heart failure. Recent studies suggest that diabetes also impairs reparative responses after cell therapy. In this study, we examined potential mechanisms by which diabetes affects cardiac progenitor cells (CPCs). CPCs isolated from the diabetic heart showed diminished proliferation, a propensity for cell death, and a pro-adipogenic phenotype. The diabetic CPCs were insulin-resistant, and they showed higher energetic reliance on glycolysis, which was associated with up-regulation of the pro-glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3). In WT CPCs, expression of a mutant form of PFKFB, which mimics PFKFB3 activity and increases glycolytic rate, was sufficient to phenocopy the mitochondrial and proliferative deficiencies found in diabetic cells. Consistent with activation of phosphofructokinase in diabetic cells, stable isotope carbon tracing in diabetic CPCs showed dysregulation of the pentose phosphate and glycero(phospho)lipid synthesis pathways. We describe diabetes-induced dysregulation of carbon partitioning using stable isotope metabolomicsbased coupling quotients, which relate relative flux values between metabolic pathways. These findings suggest that diabetes causes an imbalance in glucose carbon allocation by uncoupling biosynthetic pathway activity, which could diminish the efficacy of CPCs for myocardial repair.

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“…Thus, the model recapitulates features of the GSC observed for both mouse and human cells and can be used for analysis of pathways involved in GLUT4 trafficking in human cells. We note that during the course of this work, other laboratories developed and validated similar models of insulin-dependent GLUT4 translocation in HeLa cells (Haga et al, 2011;Trefely et al, 2015).…”

Section: Chc22mentioning

confidence: 90%

CHC22 clathrin mediates traffic from early secretory compartments for human GLUT4 pathway biogenesis

Camus

Figueras-Novoa

et al. 2018

Preprint

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Glucose Transporter 4 (GLUT4) is sequestered inside muscle and fat, then released by vesicle traffic to the cell surface in response to post-prandial insulin for blood glucose clearance. Here we map the biogenesis of this GLUT4 traffic pathway in humans, which involves clathrin isoform CHC22. We observe that GLUT4 transits through the early secretory pathway more slowly than the constitutively-secreted GLUT1 transporter and localize CHC22 to the endoplasmic-reticulum-to-Golgi-intermediate compartment (ERGIC). CHC22 functions in transport from the ERGIC, as demonstrated by an essential role in forming the replication vacuole of Legionella pneumophila bacteria, which requires ERGIC-derived membrane. CHC22 complexes with ERGIC tether p115, GLUT4 and sortilin and down-regulation of either p115 or CHC22, but not GM130 or sortilin abrogate insulin-responsive GLUT4 release. This indicates CHC22 traffic initiates human GLUT4 sequestration from the ERGIC, and defines a role for CHC22 in addition to retrograde sorting of GLUT4 after endocytic recapture, enhancing pathways for GLUT4 sequestration in humans relative to mice, which lack CHC22.SummaryBlood glucose clearance relies on insulin-mediated exocytosis of glucose transporter 4 (GLUT4) from sites of intracellular sequestration. We show that in humans, CHC22 clathrin mediates membrane traffic from the ER-to-Golgi Intermediate Compartment, which is needed for GLUT4 sequestration during GLUT4 pathway biogenesis.

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Kinome Screen Identifies PFKFB3 and Glucose Metabolism as Important Regulators of the Insulin/Insulin-like Growth Factor (IGF)-1 Signaling Pathway

Cited by 60 publications

References 103 publications

Akt mediates TIGAR induction in HeLa cells following PFKFB3 inhibition

Akt mediates TIGAR induction in HeLa cells following PFKFB3 inhibition

Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells

CHC22 clathrin mediates traffic from early secretory compartments for human GLUT4 pathway biogenesis

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