A Pharmacological Map of the Pi3-k Family Defines a Role for P110alpha in Insulin Signaling.
From: Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
Cell
- Publish Date: May 2006
- ISSN: 0092-8674
- Volume: 125
- Issue: 4
- Pages: 733-47
- Medium: Print
- Language: English
- Citation (JAMA): Knight Zachary A, Gonzalez Beatriz, Feldman Morri E, et al. A Pharmacological Map of the Pi3-k Family Defines a Role for P110alpha in Insulin Signaling.. Cell May 2006;125:733-47
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.
Mesh Headings (Keywords): 1-Phosphatidylinositol 3-Kinase, Adipose Tissue, Animals, Binding Sites, Crystallography, X-Ray, Enzyme Inhibitors, Female, Glucose, Humans, Insulin, Isoenzymes, Mice, Models, Molecular, Molecular Structure, Muscle Fibers, Phosphoproteins, Signal Transduction
Check for Full Text / PubMed Unique Identifier (PMID): 16647110
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