Forward chemical genetic approach identifies new role for GAPDH in insulin signaling

Jaeki Min, Yun Kyung Kim, Patricia G. Cipriani, Mira Kang, Sonya M. Khersonsky, Daniel P. Walsh, Ji Young Lee, Sherry Niessen, John R. Yates, Kristin Gunsalus, Fabio Piano, Young Tae Chang

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)55-59
Number of pages5
JournalNature Chemical Biology
Volume3
Issue number1
DOIs
StatePublished - Jan 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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