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Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma

BACKGROUND: Multiple myeloma (MM) is a fatal plasma cell malignancy exhibiting enhanced glucose consumption associated with an aerobic glycolytic phenotype (i.e., the Warburg effect). We have previously demonstrated that myeloma cells exhibit constitutive plasma membrane (PM) localization of GLUT4,...

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Autores principales: Cheng, Javelin C, McBrayer, Samuel K, Coarfa, Cristian, Dalva-Aydemir, Sevim, Gunaratne, Preethi H, Carpten, John D, Keats, Jonathan K, Rosen, Steven T, Shanmugam, Mala
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178207/
https://www.ncbi.nlm.nih.gov/pubmed/24280290
http://dx.doi.org/10.1186/2049-3002-1-14
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author Cheng, Javelin C
McBrayer, Samuel K
Coarfa, Cristian
Dalva-Aydemir, Sevim
Gunaratne, Preethi H
Carpten, John D
Keats, Jonathan K
Rosen, Steven T
Shanmugam, Mala
author_facet Cheng, Javelin C
McBrayer, Samuel K
Coarfa, Cristian
Dalva-Aydemir, Sevim
Gunaratne, Preethi H
Carpten, John D
Keats, Jonathan K
Rosen, Steven T
Shanmugam, Mala
author_sort Cheng, Javelin C
collection PubMed
description BACKGROUND: Multiple myeloma (MM) is a fatal plasma cell malignancy exhibiting enhanced glucose consumption associated with an aerobic glycolytic phenotype (i.e., the Warburg effect). We have previously demonstrated that myeloma cells exhibit constitutive plasma membrane (PM) localization of GLUT4, consistent with the dependence of MM cells on this transporter for maintenance of glucose consumption rates, proliferative capacity, and viability. The purpose of this study was to investigate the molecular basis of constitutive GLUT4 plasma membrane localization in MM cells. FINDINGS: We have elucidated a novel mechanism through which myeloma cells achieve constitutive GLUT4 activation involving elevated expression of the Rab-GTPase activating protein AS160_v2 splice variant to promote the Warburg effect. AS160_v2-positive MM cell lines display constitutive Thr642 phosphorylation, known to be required for inactivation of AS160 Rab-GAP activity. Importantly, we show that enforced expression of AS160_v2 is required for GLUT4 PM translocation and activation in these select MM lines. Furthermore, we demonstrate that ectopic expression of a full-length, phospho-deficient AS160 mutant is sufficient to impair constitutive GLUT4 cell surface residence, which is characteristic of MM cells. CONCLUSIONS: This is the first study to tie AS160 de-regulation to increased glucose consumption rates and the Warburg effect in cancer. Future studies investigating connections between the insulin/IGF-1/AS160_v2/GLUT4 axis and FDG-PET positivity in myeloma patients are warranted and could provide rationale for therapeutically targeting this pathway in MM patients with advanced disease.
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spelling pubmed-41782072014-10-01 Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma Cheng, Javelin C McBrayer, Samuel K Coarfa, Cristian Dalva-Aydemir, Sevim Gunaratne, Preethi H Carpten, John D Keats, Jonathan K Rosen, Steven T Shanmugam, Mala Cancer Metab Rapid Communication BACKGROUND: Multiple myeloma (MM) is a fatal plasma cell malignancy exhibiting enhanced glucose consumption associated with an aerobic glycolytic phenotype (i.e., the Warburg effect). We have previously demonstrated that myeloma cells exhibit constitutive plasma membrane (PM) localization of GLUT4, consistent with the dependence of MM cells on this transporter for maintenance of glucose consumption rates, proliferative capacity, and viability. The purpose of this study was to investigate the molecular basis of constitutive GLUT4 plasma membrane localization in MM cells. FINDINGS: We have elucidated a novel mechanism through which myeloma cells achieve constitutive GLUT4 activation involving elevated expression of the Rab-GTPase activating protein AS160_v2 splice variant to promote the Warburg effect. AS160_v2-positive MM cell lines display constitutive Thr642 phosphorylation, known to be required for inactivation of AS160 Rab-GAP activity. Importantly, we show that enforced expression of AS160_v2 is required for GLUT4 PM translocation and activation in these select MM lines. Furthermore, we demonstrate that ectopic expression of a full-length, phospho-deficient AS160 mutant is sufficient to impair constitutive GLUT4 cell surface residence, which is characteristic of MM cells. CONCLUSIONS: This is the first study to tie AS160 de-regulation to increased glucose consumption rates and the Warburg effect in cancer. Future studies investigating connections between the insulin/IGF-1/AS160_v2/GLUT4 axis and FDG-PET positivity in myeloma patients are warranted and could provide rationale for therapeutically targeting this pathway in MM patients with advanced disease. BioMed Central 2013-05-29 /pmc/articles/PMC4178207/ /pubmed/24280290 http://dx.doi.org/10.1186/2049-3002-1-14 Text en Copyright © 2013 Cheng et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Rapid Communication
Cheng, Javelin C
McBrayer, Samuel K
Coarfa, Cristian
Dalva-Aydemir, Sevim
Gunaratne, Preethi H
Carpten, John D
Keats, Jonathan K
Rosen, Steven T
Shanmugam, Mala
Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma
title Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma
title_full Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma
title_fullStr Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma
title_full_unstemmed Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma
title_short Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma
title_sort expression and phosphorylation of the as160_v2 splice variant supports glut4 activation and the warburg effect in multiple myeloma
topic Rapid Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178207/
https://www.ncbi.nlm.nih.gov/pubmed/24280290
http://dx.doi.org/10.1186/2049-3002-1-14
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