TY - JOUR
T1 - Forward chemical genetic approach identifies new role for GAPDH in insulin signaling
AU - Min, Jaeki
AU - Kyung Kim, Yun
AU - Cipriani, Patricia G.
AU - Kang, Mira
AU - Khersonsky, Sonya M.
AU - Walsh, Daniel P.
AU - Lee, Ji Young
AU - Niessen, Sherry
AU - Yates, John R.
AU - Gunsalus, Kristin
AU - Piano, Fabio
AU - Chang, Young Tae
N1 - Funding Information:
We gratefully acknowledge the support of the US National Institutes of Health (NIH) (R01-CA096912), and the US National Science Foundation equipment grants for the NMR (MRI-0116222) and the capillary LC ion trap mass spectrometer (CHE-0234863). Components of this work were conducted in a Shared Instrumentation Facility constructed with support from Research Facilities Improvement grant C06 RR-16572 from the US National Center for Research Resources and the US NIH. J.R.Y. is supported by US NIH grant P41RR11823-10.
PY - 2007/1
Y1 - 2007/1
N2 - Insulin and insulin-like growth factor have an essential role in growth, development and the maintenance of metabolic homeostasis, including glucose uptake from the bloodstream. Researchers have identified mutations in insulin receptors that cause severe insulin resistance, and a temperature-sensitive daf-2 (a gene encoding an insulin receptor-like protein) mutant in Caenorhabditis elegans has served as an insulin resistance model. Here we report a forward chemical genetic approach with a tagged library that we used to identify a small molecule, GAPDH segregator (GAPDS), that suppresses the dauer formation induced by the daf-2 mutant. Like insulin, GAPDS increased both glucose uptake and the concentration of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) in mammalian preadipocytes. Using affinity matrices and RNA interference, we identified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a GAPDS target. We discovered that GAPDH stimulates phosphatase activity against not only PtdIns(3,4,5)P3 but also PtdIns(4,5)P2. These results suggest that GAPDH is both an active regulator in the phosphoinositide-mediated signaling pathway and a potential new target for insulin resistance treatment.
AB - Insulin and insulin-like growth factor have an essential role in growth, development and the maintenance of metabolic homeostasis, including glucose uptake from the bloodstream. Researchers have identified mutations in insulin receptors that cause severe insulin resistance, and a temperature-sensitive daf-2 (a gene encoding an insulin receptor-like protein) mutant in Caenorhabditis elegans has served as an insulin resistance model. Here we report a forward chemical genetic approach with a tagged library that we used to identify a small molecule, GAPDH segregator (GAPDS), that suppresses the dauer formation induced by the daf-2 mutant. Like insulin, GAPDS increased both glucose uptake and the concentration of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) in mammalian preadipocytes. Using affinity matrices and RNA interference, we identified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a GAPDS target. We discovered that GAPDH stimulates phosphatase activity against not only PtdIns(3,4,5)P3 but also PtdIns(4,5)P2. These results suggest that GAPDH is both an active regulator in the phosphoinositide-mediated signaling pathway and a potential new target for insulin resistance treatment.
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U2 - 10.1038/nchembio833
DO - 10.1038/nchembio833
M3 - Article
C2 - 17115034
AN - SCOPUS:33845789522
SN - 1552-4450
VL - 3
SP - 55
EP - 59
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 1
ER -