Profibrotic up-regulation of glucose transporter 1 by TGF-β involves activation of MEK and mammalian target of rapamycin complex 2 pathways

Mahefatiana Andrianifahanana, Danielle M. Hernandez, Xueqian Yin, Jeong Han Kang, Mi Yeon Jung, Youli Wang, Eunhee S. Yi, Anja C. Roden, Andrew H. Limper, Edward B. Leof

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

TGF-β plays a central role in the pathogenesis of fibroproliferative disorders. Defining the exact underlyingmolecularbasis is therefore critical for thedevelopment of viable therapeutic strategies.Here,we showthat expressionof the facilitative glucose transporter 1 (GLUT1) is inducedbyTGF-βin fibroblast lines andprimary cells and is required for the profibrotic effects of TGF-β. In addition, enhancedGLUT1 expression is observed in fibrotic areas of lungs of both patients with idiopathic pulmonary fibrosis and mice that are subjected to a fibrosis-inducing bleomycin treatment. By using pharmacologic and genetic approaches, we demonstrate that up-regulation of GLUT1 occurs via the canonical Smad2/3 pathway and requires autocrine activation of the receptor tyrosine kinases, platelet-derived and epidermal growth factor receptors. Engagement of the common downstream effector PI3K subsequently triggers activation of the MEK and mammalian target of rapamycin complex 2, which cooperate in regulating GLUT1 expression. Of note, inhibition of GLUT1 activity and/or expression is shown to impair TGFβ-driven fibrogenic processes, including cell proliferation and production of profibrotic mediators. These findings provide new perspectives on the interrelation of metabolism and profibrotic TGF-β signaling and present opportunities for potential therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)3733-3744
Number of pages12
JournalFASEB Journal
Volume30
Issue number11
DOIs
StatePublished - Nov 2016

Keywords

  • Fibrosis
  • Metabolism
  • Signaling

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Andrianifahanana, M., Hernandez, D. M., Yin, X., Kang, J. H., Jung, M. Y., Wang, Y., Yi, E. S., Roden, A. C., Limper, A. H., & Leof, E. B. (2016). Profibrotic up-regulation of glucose transporter 1 by TGF-β involves activation of MEK and mammalian target of rapamycin complex 2 pathways. FASEB Journal, 30(11), 3733-3744. https://doi.org/10.1096/fj.201600428R