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

Hai Hu; Ashish Juvekar; Costas A. Lyssiotis; Evan C. Lien; John G. 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

doi:10.1016/j.cell.2015.12.042

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

Hai Hu, Ashish Juvekar, Costas A. Lyssiotis, Evan C. Lien, John G. 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

School of Medicine

Research output: Contribution to journal › Article › peer-review

148 Scopus citations

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 language	English (US)
Pages (from-to)	433-446
Number of pages	14
Journal	Cell
Volume	164
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2015.12.042
State	Published - Jan 28 2016

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Hu, H., Juvekar, A., Lyssiotis, C. A., Lien, E. C., Albeck, J. G., Oh, D., Varma, G., Hung, Y. P., Ullas, S., Lauring, J., Seth, P., Lundquist, M. R., Tolan, D. R., Grant, A. K., Needleman, D. J., Asara, J. M., Cantley, L. C., & Wulf, G. M. (2016). Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton. Cell, 164(3), 433-446. https://doi.org/10.1016/j.cell.2015.12.042

Hu, H, Juvekar, A, Lyssiotis, CA, Lien, EC, Albeck, JG, 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

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title = "Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton",

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.",

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

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AU - Hu, Hai

AU - Juvekar, Ashish

AU - Lyssiotis, Costas A.

AU - Lien, Evan C.

AU - Albeck, John G.

AU - Oh, Doogie

AU - Varma, Gopal

AU - Hung, Yin Pun

AU - Ullas, Soumya

AU - Lauring, Josh

AU - Seth, Pankaj

AU - Lundquist, Mark R.

AU - Tolan, Dean R.

AU - Grant, Aaron K.

AU - Needleman, Daniel J.

AU - Asara, John M.

AU - Cantley, Lewis C.

AU - Wulf, Gerburg M.

PY - 2016/1/28

Y1 - 2016/1/28

N2 - 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.

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

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