Abstract
PHLPP2 is a member of the PHLPP family of phosphatases, known to suppress cell growth by inhibiting proliferation or promoting apoptosis. Oncogenic kinases Akt, S6K, and PKC, and pro-apoptotic kinase Mst1, have been recognized as functional targets of the PHLPP family. However, we observed that, in T-leukemia cells subjected to metabolic stress from glucose limitation, PHLPP2 specifically targets the energy-sensing AMP-activated protein kinase, pAMPK, rather than Akt or S6K. PHLPP2 dephosphorylates pAMPK in several other human cancer cells as well. PHLPP2 and pAMPK interact with each other, and the pleckstrin homology (PH) domain on PHLPP2 is required for their interaction, for dephosphorylating and inactivating AMPK, and for the apoptotic response of the leukemia cells to glucose limitation. Silencing PHLPP2 protein expression prolongs the survival of leukemia cells subjected to severe glucose limitation by promoting a switch to AMPK-mediated fatty acid oxidation for energy generation. Thus, this study reveals a novel role for PHLPP2 in suppressing a survival response mediated through AMPK signaling. Given the multiple ways in which PHLPP phosphatases act to oppose survival signaling in cancers and the pivotal role played by AMPK in redox homeostasis via glucose and fatty acid metabolism, the revelation that AMPK is a target of PHLPP2 could lead to better therapeutics directed both at cancer and at metabolic diseases.
| Original language | English (US) |
|---|---|
| Article number | 904 |
| Journal | Cell Death and Disease |
| Volume | 12 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2021 |
Bibliographical note
Funding Information:This study was supported by NIH grant R01 CA157971 and MN Partnership Infrastructure Award MNP IF #16.09 (to AK), by R01s DK114401, DK108790, AG055452, and American Diabetes Association grant 1-16-IBS-203 (to DGM) and grant U24 DK097153 to the University of Michigan Metabolomics Core, MRC2. YY was supported by a Doctoral Dissertation Fellowship from the University of Minnesota.
Funding Information:
The authors thank Drs. Eric Hanse and Do-Hyung Kim for stimulating discussions, Dr. Alexandra Newton for providing the PHLPP2 inhibitor, and Dr. Christopher Jenness for constructing deletion mutants. The authors acknowledge the support of the Flow Cytometry Core (UFCR) at the University of Minnesota and Masonic Cancer Center (MCC), as well as the University of Michigan Metabolomics Core.
Publisher Copyright:
© 2021, The Author(s).
