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

Cell. 2016 Jan 28;164(3):433-46. doi: 10.1016/j.cell.2015.12.042.

Authors

Hai Hu¹, Ashish Juvekar¹, Costas A Lyssiotis², Evan C Lien³, John G Albeck⁴, Doogie Oh⁵, Gopal Varma⁶, Yin Pun Hung⁷, Soumya Ullas⁸, Josh Lauring⁹, Pankaj Seth¹⁰, Mark R Lundquist², Dean R Tolan¹¹, Aaron K Grant⁶, Daniel J Needleman⁵, John M Asara¹², Lewis C Cantley², Gerburg M Wulf¹³

Affiliations

¹ Division of Hematology and Oncology, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS), Boston, MA 02215, USA.
² Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
³ Department of Pathology, BIDMC, Boston, MA 02215, USA.
⁴ Department of Cell Biology, HMS, Boston, MA 02215, USA.
⁵ Department of Molecular and Cellular Biology, FAS Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.
⁶ Department of Radiology, BIDMC Boston, MA 02215, USA.
⁷ Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁸ Longwood Small Animal Imaging Facility, BIDMC, Boston, MA 02215, USA.
⁹ The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
¹⁰ Division of Interdisciplinary Medicine, BIDMC, Boston, MA 02215, USA.
¹¹ Department of Biology, Boston University, Boston, MA 02215, USA.
¹² Division of Signal Transduction, BIDMC, Boston, MA 02215, USA.
¹³ Division of Hematology and Oncology, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS), Boston, MA 02215, USA. Electronic address: gwulf@bidmc.harvard.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Breast Neoplasms / metabolism
Cell Line, Tumor
Cytoskeleton / metabolism
Cytosol / metabolism
Disease Models, Animal
Epithelial Cells / metabolism
Fructose-Bisphosphate Aldolase / metabolism*
Glycolysis
Humans
Insulin / metabolism
Mice
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoinositide-3 Kinase Inhibitors
Signal Transduction

Substances

Insulin
Phosphoinositide-3 Kinase Inhibitors
Fructose-Bisphosphate Aldolase

Abstract

Publication types

MeSH terms

Substances

Grants and funding