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A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling

Knight, Zachary A
Gonzalez, Beatriz
Feldman, Morri E
Zunder, Eli R
Goldenberg, David D
Williams, Olusegun
Stokoe, David
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Published in Cell. 2006, vol. 125, no. 4, p. 733-47
Abstract Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-K family. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitors bound to p110gamma identify a conformationally mobile region that is uniquely exploited by selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling. We find that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110alpha activity. Compounds targeting p110alpha block the acute effects of insulin treatment in vivo, whereas a p110beta inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family.
Keywords Adipose Tissue/cytologyAnimalsBinding SitesCrystallography, X-RayEnzyme Inhibitors/chemistry/metabolismFemaleGlucose/metabolismHumansInsulin/metabolismInsulin Receptor Substrate ProteinsIsoenzymes/antagonists & inhibitors/chemistry/genetics/metabolismMiceModels, MolecularMolecular StructureMuscle Fibers, Skeletal/metabolismPhosphatidylinositol 3-Kinases/antagonists & inhibitors/chemistry/genetics/metabolismPhosphoproteins/metabolismSignal Transduction/physiology
PMID: 16647110
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KNIGHT, Zachary A et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. In: Cell, 2006, vol. 125, n° 4, p. 733-47. doi: 10.1016/j.cell.2006.03.035 https://archive-ouverte.unige.ch/unige:18228

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Deposited on : 2012-01-30

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