rdf:type |
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lifeskim:mentions |
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pubmed:issue |
4
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pubmed:dateCreated |
2006-5-22
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
|
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/1-phosphatidylinositol 3-kinase...,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Glucose,
http://linkedlifedata.com/resource/pubmed/chemical/IRS1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin Receptor Substrate Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Irs1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Isoenzymes,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoproteins
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0092-8674
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pubmed:author |
pubmed-author:BallaAndrasA,
pubmed-author:BallaTamasT,
pubmed-author:FeldmanMorri EME,
pubmed-author:GoldenbergDavid DDD,
pubmed-author:GonzalezBeatrizB,
pubmed-author:KnightZachary AZA,
pubmed-author:LoewithRobbieR,
pubmed-author:ShokatKevan MKM,
pubmed-author:StokoeDavidD,
pubmed-author:TothBalazsB,
pubmed-author:WeissWilliam AWA,
pubmed-author:WilliamsOlusegunO,
pubmed-author:WilliamsRoger LRL,
pubmed-author:ZunderEli RER
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pubmed:issnType |
Print
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pubmed:day |
19
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pubmed:volume |
125
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
733-47
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:16647110-Adipose Tissue,
pubmed-meshheading:16647110-Animals,
pubmed-meshheading:16647110-Binding Sites,
pubmed-meshheading:16647110-Crystallography, X-Ray,
pubmed-meshheading:16647110-Enzyme Inhibitors,
pubmed-meshheading:16647110-Female,
pubmed-meshheading:16647110-Glucose,
pubmed-meshheading:16647110-Humans,
pubmed-meshheading:16647110-Insulin,
pubmed-meshheading:16647110-Insulin Receptor Substrate Proteins,
pubmed-meshheading:16647110-Isoenzymes,
pubmed-meshheading:16647110-Mice,
pubmed-meshheading:16647110-Models, Molecular,
pubmed-meshheading:16647110-Molecular Structure,
pubmed-meshheading:16647110-Muscle Fibers, Skeletal,
pubmed-meshheading:16647110-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:16647110-Phosphoproteins,
pubmed-meshheading:16647110-Signal Transduction
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pubmed:year |
2006
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pubmed:articleTitle |
A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.
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pubmed:affiliation |
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural,
Research Support, N.I.H., Intramural
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