Phenylarsine oxide inhibits insulin activation of phosphatidylinositol 3'-kinase.
Two early events downstream of insulin receptor autophosphorylation that are necessary for activation of glucose transport in adipocytes appear to be: (1) The tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) which (2) recruits and activates phosphatidylinositol 3'-kinase (PI3'-K). Phenylarsine oxide (PAO) has long been known to inhibit glucose transport, without inhibiting insulin receptor auto- or substrate phosphorylation. However, the PAO-sensitive site downstream of these early regulatory eventshas not been identified. Here we provide evidence that exposure of 3T3-L1 adipocytes to PAO inhibits PI3'-K activation, but it does not decrease either IRS-1 tyrosine-phosphorylation or the recruitment of PI3'-K to IRS-1 after insulin stimulation. PAO is also shown to inhibit PI3'-K activity in vitro. Therefore, since PI3'-K activation is essential for insulin stimulation of glucose transport, our results demonstrate that PI3'-K is a PAO-sensitive target of the insulin signaling pathway regulating glucose transport.
Han
Y P
YP
Department of Biochemistry, Mount Sinai School of Medicine, New York, New York 10029, USA.
Kohanski
R A
RA
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007329:Insulin Antagonists / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism
D001152:Arsenicals; D004791:Enzyme Inhibitors; D007328:Insulin; D007329:Insulin Antagonists; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; C029341:oxophenylarsine; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose