Letter abstract
Nature Chemical Biology 3, 55 - 59 (2006)
Published online: 19 November 2006 | doi:10.1038/nchembio833
Forward chemical genetic approach identifies new role for GAPDH in insulin signaling
Jaeki Min1,4, Yun Kyung Kim1,4, Patricia G Cipriani2, Mira Kang1, Sonya M Khersonsky1, Daniel P Walsh1, Ji-Young Lee1, Sherry Niessen3, John R Yates, III3, Kristin Gunsalus2, Fabio Piano2 & Young-Tae Chang1
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 resistance1, and a temperature-sensitive daf-2 (a gene encoding an insulin receptor–like protein) mutant in Caenorhabditis elegans has served as an insulin resistance model2. 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.
- Department of Chemistry, New York University, New York, New York 10003, USA.
- Department of Biology, New York University, New York, New York 10003, USA.
- Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
- These authors contributed equally to this work.
Correspondence to: Young-Tae Chang1 e-mail: yt.chang@nyu.edu
