Forward chemical genetic approach identifies new role for GAPDH in insulin signaling.
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.
Min
Jaeki
J
Department of Chemistry, New York University, New York, New York 10003, USA.
Kyung Kim
Yun
Y
Cipriani
Patricia G
PG
Kang
Mira
M
Khersonsky
Sonya M
SM
Walsh
Daniel P
DP
Lee
Ji-Young
JY
Niessen
Sherry
S
Yates
John R
JR
Gunsalus
Kristin
K
Piano
Fabio
F
Chang
Young-Tae
YT
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*
D007328:Insulin; D010716:Phosphatidylinositols; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases