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

Zachary A. Knight, Beatriz Gonzalez, Morri E. Feldman, Eli R. Zunder, David D. Goldenberg, Olusegun Williams, Robbie Loewith, David Stokoe, A. Balla, Balazs Toth, Tamas Balla, William A. Weiss, Roger L. Williams, Kevan M. Shokat

Research output: Contribution to journalArticle

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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 p110γ 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 p110α is the primary insulin-responsive PI3-K in cultured cells, whereas p110β is dispensable but sets a phenotypic threshold for p110α activity. Compounds targeting p110α block the acute effects of insulin treatment in vivo, whereas a p110β inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family.

Original languageEnglish
Pages (from-to)733-747
Number of pages15
JournalCell
Volume125
Issue number4
DOIs
Publication statusPublished - May 19 2006

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Pharmacology
Insulin
Protein Isoforms
1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
Cultured Cells
Phosphotransferases
Crystal structure
Cells
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Knight, Z. A., Gonzalez, B., Feldman, M. E., Zunder, E. R., Goldenberg, D. D., Williams, O., ... Shokat, K. M. (2006). A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling. Cell, 125(4), 733-747. https://doi.org/10.1016/j.cell.2006.03.035

A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling. / Knight, Zachary A.; Gonzalez, Beatriz; Feldman, Morri E.; Zunder, Eli R.; Goldenberg, David D.; Williams, Olusegun; Loewith, Robbie; Stokoe, David; Balla, A.; Toth, Balazs; Balla, Tamas; Weiss, William A.; Williams, Roger L.; Shokat, Kevan M.

In: Cell, Vol. 125, No. 4, 19.05.2006, p. 733-747.

Research output: Contribution to journalArticle

Knight, ZA, Gonzalez, B, Feldman, ME, Zunder, ER, Goldenberg, DD, Williams, O, Loewith, R, Stokoe, D, Balla, A, Toth, B, Balla, T, Weiss, WA, Williams, RL & Shokat, KM 2006, 'A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling', Cell, vol. 125, no. 4, pp. 733-747. https://doi.org/10.1016/j.cell.2006.03.035
Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O et al. A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling. Cell. 2006 May 19;125(4):733-747. https://doi.org/10.1016/j.cell.2006.03.035
Knight, Zachary A. ; Gonzalez, Beatriz ; Feldman, Morri E. ; Zunder, Eli R. ; Goldenberg, David D. ; Williams, Olusegun ; Loewith, Robbie ; Stokoe, David ; Balla, A. ; Toth, Balazs ; Balla, Tamas ; Weiss, William A. ; Williams, Roger L. ; Shokat, Kevan M. / A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling. In: Cell. 2006 ; Vol. 125, No. 4. pp. 733-747.
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