Phosphatase PHLPP2 regulates the cellular response to metabolic stress through AMPK

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.

RNA‐Seq‐based discovery of genetic variants and allele‐specific expression of two layer lines and broiler chicken

“…The other genes VPS9D1 (GTPase activator activity and transporter activity), PDP2 (pyruvate metabolism,Gray, 2014), CMTM4 (cytokine activity,Tan et al, 2022), and PHLPP22 (protein regulating the cell's response to metabolic stress via the AMPK pathway,Yan et al, 2021) are mainly involved in immunological processes and energy metabolism, confirming previous findings that both strains use different strategies to maintain their immunity and metabolic activity under highperformance conditions.F I G U R E 9Allele-specific expression within LB and LSL at different time points. (a) An upset plot indicates the number of genes with ASE within LB and LSL at weeks 10, 16, 24, 30, and 60.…”

Exosomal EPHA2 derived from highly metastatic breast cancer cells promotes angiogenesis by activating the AMPK signaling pathway through Ephrin A1-EPHA2 forward signaling

“…In addition, in Ephrin A1-silenced endothelial cells, exosomal EPHA2 could not induce an elevation in phosphorylation of AMPK, further supporting the role of AMPK downstream of Ephrin A1-EPHA2 signaling. AMPK is known as a cellular energy regulator 51 , 52 . Several studies have shown that AMPK is involved in regulating the function of vascular endothelial cells and angiogenesis under pathological conditions.…”

Signaling pathways and intervention for therapy of type 2 diabetes mellitus

“…100,105 Such potent effects of the AMPK pathway in cellular metabolism and functions are prone to endow it with an incredible significance in the peripheral insulin action, glucose uptake, nutrient intake, lipid metabolism, inflammation, insulin secretion, and thus systematic homeostasis of glucose and lipids, warranting the vigorous attention of its therapeutic potential in the area of T2DM. 104 Degrading of AMPK activity is widely observed in the skeletal muscle from mice and humans with obesity and T2DM, probably due to that high glucose could inhibit the AMPK activity by breaking the active LKB1 complex, 106 activating the protein phosphatase PP2A, 107 upregulating the phosphatase PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2), 108 and inducing ubiquitination degradation of AMPK subunits. 109,110 AMPK activation has been found to exert constructive effects on the glucose uptake of skeletal muscle, and regarding this, the deficiency of muscular AMPK activity might compromise the whole-body glucose homeostasis during T2DM.…”

“…Degrading of AMPK activity is widely observed in the skeletal muscle from mice and humans with obesity and T2DM, probably due to that high glucose could inhibit the AMPK activity by breaking the active LKB1 complex, 106 activating the protein phosphatase PP2A, 107 upregulating the phosphatase PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2), 108 and inducing ubiquitination degradation of AMPK subunits. 109 , 110 AMPK activation has been found to exert constructive effects on the glucose uptake of skeletal muscle, and regarding this, the deficiency of muscular AMPK activity might compromise the whole‐body glucose homeostasis during T2DM.…”