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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.
Trefely, Sophie; Khoo, Poh-Sim; Krycer, James R; Chaudhuri, Rima; Fazakerley, Daniel J; Parker, Benjamin L; Sultani, Ghazal; Lee, James; Stephan, Jean-Philippe; Torres, Eric; Jung, Kenneth; Kuijl, Coenraad; James, David E; Junutula, Jagath R; Stöckli, Jacqueline.
Afiliação
  • Trefely S; From the Garvan Institute of Medical Research, Sydney 2010 NSW, Australia.
  • Khoo PS; From the Garvan Institute of Medical Research, Sydney 2010 NSW, Australia, Genentech Inc., South San Francisco, California 94080.
  • Krycer JR; the Charles Perkins Centre, School of Molecular Bioscience, University of Sydney, Sydney 2006 NSW, Australia, and.
  • Chaudhuri R; the Charles Perkins Centre, School of Molecular Bioscience, University of Sydney, Sydney 2006 NSW, Australia, and.
  • Fazakerley DJ; the Charles Perkins Centre, School of Molecular Bioscience, University of Sydney, Sydney 2006 NSW, Australia, and.
  • Parker BL; the Charles Perkins Centre, School of Molecular Bioscience, University of Sydney, Sydney 2006 NSW, Australia, and.
  • Sultani G; From the Garvan Institute of Medical Research, Sydney 2010 NSW, Australia.
  • Lee J; Genentech Inc., South San Francisco, California 94080.
  • Stephan JP; Genentech Inc., South San Francisco, California 94080.
  • Torres E; Genentech Inc., South San Francisco, California 94080.
  • Jung K; Genentech Inc., South San Francisco, California 94080.
  • Kuijl C; Genentech Inc., South San Francisco, California 94080.
  • James DE; the Charles Perkins Centre, School of Molecular Bioscience, University of Sydney, Sydney 2006 NSW, Australia, and the Sydney Medical School, University of Sydney, Sydney 2006 NSW, Australia david.james@sydney.edu.au.
  • Junutula JR; Genentech Inc., South San Francisco, California 94080, jagathjr@gmail.com.
  • Stöckli J; the Charles Perkins Centre, School of Molecular Bioscience, University of Sydney, Sydney 2006 NSW, Australia, and jacqueline.stoeckli@sydney.edu.au.
J Biol Chem ; 290(43): 25834-46, 2015 Oct 23.
Article em En | MEDLINE | ID: mdl-26342081
The insulin/insulin-like growth factor (IGF)-1 signaling pathway (ISP) plays a fundamental role in long term health in a range of organisms. Protein kinases including Akt and ERK are intimately involved in the ISP. To identify other kinases that may participate in this pathway or intersect with it in a regulatory manner, we performed a whole kinome (779 kinases) siRNA screen for positive or negative regulators of the ISP, using GLUT4 translocation to the cell surface as an output for pathway activity. We identified PFKFB3, a positive regulator of glycolysis that is highly expressed in cancer cells and adipocytes, as a positive ISP regulator. Pharmacological inhibition of PFKFB3 suppressed insulin-stimulated glucose uptake, GLUT4 translocation, and Akt signaling in 3T3-L1 adipocytes. In contrast, overexpression of PFKFB3 in HEK293 cells potentiated insulin-dependent phosphorylation of Akt and Akt substrates. Furthermore, pharmacological modulation of glycolysis in 3T3-L1 adipocytes affected Akt phosphorylation. These data add to an emerging body of evidence that metabolism plays a central role in regulating numerous biological processes including the ISP. Our findings have important implications for diseases such as type 2 diabetes and cancer that are characterized by marked disruption of both metabolism and growth factor signaling.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Proteínas Quinases / Fator de Crescimento Insulin-Like I / Transdução de Sinais / Fosfofrutoquinase-2 / Glucose / Insulina Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Austrália

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Proteínas Quinases / Fator de Crescimento Insulin-Like I / Transdução de Sinais / Fosfofrutoquinase-2 / Glucose / Insulina Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Austrália