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Cited by 1,174PI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and CancerProtein Kinase Regulation and GTPase Signaling

A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling

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Knight, Zachary A., Gonzalez, Beatriz, Feldman, Morri E., Zunder, Eli R., Goldenberg, David D., Williams, Olusegun, Loewith, Robbie, Stokoe, David +6 more·2006·Cell
DOI 10.1016/j.cell.2006.03.035PMC PMC2946820
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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.

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  • p110α heterodimers play a key role in glucose homeostasis and in insulin and growth factor signalling.

    “p110α heterodimers play a key role in glucose homeostasis and in insulin and growth factor signalling [65–67].”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [66]

    In “Functional Inhibition of Glucose Transport in Cells and Animals” (page unavailable), p110α inhibition blocks insulin-stimulated glucose uptake in adipocytes and the acute fall in blood glucose in mice, supporting a key role in insulin signalling and acute glucose regulation. The Discussion (page unavailable) cautions that chronic glucose homeostasis remains to be investigated. Our copy does not establish the additional claim specifically about p110α heterodimers in growth-factor signalling. (LLM, conf=0.83)

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Authors
Knight, Z. A., Gonzalez, B., Feldman, M. E., Zunder, E. R., Goldenberg, D. D., Williams, O., Loewith, R., Stokoe, D., Balla, A., Toth, B., Balla, T., Weiss, W. A., Williams, R. L., & Shokat, K. M.
Affiliations
  • Howard Hughes Medical Institute (US)
  • University of California, San Francisco (US)
  • University of Geneva (CH)
  • MRC Laboratory of Molecular Biology (GB)
Corresponding author
Shokat, Kevan M.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2006-05
Volume
125
Issue
4
Pages
733-747
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2006.03.035
PMC
PMC2946820
OpenAlex
W2124593509
Cited by
1,174
References
1
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FWCI
37.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
  • PubMed Central (acceptedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders
  • Howard Hughes Medical Institute
  • European Synchrotron Radiation Facility
  • National Institutes of Health
  • Medical Research Council
  • National Institute of Allergy and Infectious Diseases (AI 44009, R01AI044009)
  • European Social Fund
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
phosphatidylinositol 3-kinase, p110α, p110β, p110γ, insulin signaling, target selectivity, target validation, therapeutic target
MeSH terms
Phosphoinositide-3 Kinase Inhibitors, Adipose Tissue, Animals, Binding Sites, Enzyme Inhibitors, Female, Glucose, Humans, Insulin, Isoenzymes, Models, Molecular, Phosphoproteins, Molecular Structure, Signal Transduction, Crystallography, X-Ray, Muscle Fibers, Skeletal, Phosphatidylinositol 3-Kinases, Mice, Insulin Receptor Substrate Proteins, Class I Phosphatidylinositol 3-Kinases

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