Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton

Hai Hu, Ashish Juvekar, Costas A. Lyssiotis, Evan C. Lien, John Albeck, Doogie Oh, Gopal Varma, Yin Pun Hung, Soumya Ullas, Josh Lauring, Pankaj Seth, Mark R. Lundquist, Dean R. Tolan, Aaron K. Grant, Daniel J. Needleman, John M. Asara, Lewis C. Cantley, Gerburg M. Wulf

Research output: Contribution to journalArticle

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Abstract

Summary The phosphoinositide 3-kinase (PI3K) pathway regulates multiple steps in glucose metabolism and also cytoskeletal functions, such as cell movement and attachment. Here, we show that PI3K directly coordinates glycolysis with cytoskeletal dynamics in an AKT-independent manner. Growth factors or insulin stimulate the PI3K-dependent activation of Rac, leading to disruption of the actin cytoskeleton, release of filamentous actin-bound aldolase A, and an increase in aldolase activity. Consistently, PI3K inhibitors, but not AKT, SGK, or mTOR inhibitors, cause a significant decrease in glycolysis at the step catalyzed by aldolase, while activating PIK3CA mutations have the opposite effect. These results point toward a master regulatory function of PI3K that integrates an epithelial cell's metabolism and its form, shape, and function, coordinating glycolysis with the energy-intensive dynamics of actin remodeling.

Original languageEnglish (US)
Pages (from-to)433-446
Number of pages14
JournalCell
Volume164
Issue number3
DOIs
StatePublished - Jan 28 2016

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Fructose-Bisphosphate Aldolase
1-Phosphatidylinositol 4-Kinase
Glycolysis
Phosphatidylinositols
Actin Cytoskeleton
Actins
Phosphotransferases
Metabolism
Cell Movement
Intercellular Signaling Peptides and Proteins
Epithelial Cells
Chemical activation
Cells
Insulin
Glucose
Mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton. / Hu, Hai; Juvekar, Ashish; Lyssiotis, Costas A.; Lien, Evan C.; Albeck, John; Oh, Doogie; Varma, Gopal; Hung, Yin Pun; Ullas, Soumya; Lauring, Josh; Seth, Pankaj; Lundquist, Mark R.; Tolan, Dean R.; Grant, Aaron K.; Needleman, Daniel J.; Asara, John M.; Cantley, Lewis C.; Wulf, Gerburg M.

In: Cell, Vol. 164, No. 3, 28.01.2016, p. 433-446.

Research output: Contribution to journalArticle

Hu, H, Juvekar, A, Lyssiotis, CA, Lien, EC, Albeck, J, Oh, D, Varma, G, Hung, YP, Ullas, S, Lauring, J, Seth, P, Lundquist, MR, Tolan, DR, Grant, AK, Needleman, DJ, Asara, JM, Cantley, LC & Wulf, GM 2016, 'Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton', Cell, vol. 164, no. 3, pp. 433-446. https://doi.org/10.1016/j.cell.2015.12.042
Hu, Hai ; Juvekar, Ashish ; Lyssiotis, Costas A. ; Lien, Evan C. ; Albeck, John ; Oh, Doogie ; Varma, Gopal ; Hung, Yin Pun ; Ullas, Soumya ; Lauring, Josh ; Seth, Pankaj ; Lundquist, Mark R. ; Tolan, Dean R. ; Grant, Aaron K. ; Needleman, Daniel J. ; Asara, John M. ; Cantley, Lewis C. ; Wulf, Gerburg M. / Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton. In: Cell. 2016 ; Vol. 164, No. 3. pp. 433-446.
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AU - Oh, Doogie

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AU - Lundquist, Mark R.

AU - Tolan, Dean R.

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AB - Summary The phosphoinositide 3-kinase (PI3K) pathway regulates multiple steps in glucose metabolism and also cytoskeletal functions, such as cell movement and attachment. Here, we show that PI3K directly coordinates glycolysis with cytoskeletal dynamics in an AKT-independent manner. Growth factors or insulin stimulate the PI3K-dependent activation of Rac, leading to disruption of the actin cytoskeleton, release of filamentous actin-bound aldolase A, and an increase in aldolase activity. Consistently, PI3K inhibitors, but not AKT, SGK, or mTOR inhibitors, cause a significant decrease in glycolysis at the step catalyzed by aldolase, while activating PIK3CA mutations have the opposite effect. These results point toward a master regulatory function of PI3K that integrates an epithelial cell's metabolism and its form, shape, and function, coordinating glycolysis with the energy-intensive dynamics of actin remodeling.

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