Kinome Screen Identifies PFKFB3 and Glucose Metabolism as Important Regulators of the Insulin/Insulin-like Growth Factor (IGF)-1 Signaling Pathway
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.
|ISBN||1083-351X (Electronic) 0021-9258 (Linking)|
|Authors||Trefely, S. ; Khoo, P. S. ; Krycer, J. R. ; Chaudhuri, R. ; Fazakerley, D. J. ; Parker, B. L. ; Sultani, G. ; Lee, J. ; Stephan, J. P. ; Torres, E. ; Jung, K. ; Kuijl, C. ; James, D. E. ; Junutula, J. R. ; Stockli, J.;|
|Responsible Garvan Author|
|Publisher Name||JOURNAL OF BIOLOGICAL CHEMISTRY|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/26342081|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13328|