title: Forward chemical genetic approach identifies new role for GAPDH in insulin signaling.
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)P(3)) 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)P(3) but also PtdIns(4,5)P(2). 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.
authors.affiliation: Department of Chemistry, New York University, New York, New York 10003, USA.
authors.forename: Jaeki
authors.initials: J
authors.lastname: Min
authors.forename: Yun
authors.initials: Y
authors.lastname: Kyung Kim
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Cipriani
authors.forename: Mira
authors.initials: M
authors.lastname: Kang
authors.forename: Sonya M
authors.initials: SM
authors.lastname: Khersonsky
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Walsh
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Sherry
authors.initials: S
authors.lastname: Niessen
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Kristin
authors.initials: K
authors.lastname: Gunsalus
authors.forename: Fabio
authors.initials: F
authors.lastname: Piano
authors.forename: Young-Tae
authors.initials: YT
authors.lastname: Chang
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D015394:Molecular Structure; D010716:Phosphatidylinositols / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D007328:Insulin; D010716:Phosphatidylinositols; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases