γ-6-Phosphogluconolactone, a Byproduct of the Oxidative Pentose Phosphate Pathway, Contributes to AMPK Activation through Inhibition of PP2A.
A549 Cells
AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases
/ metabolism
Animals
Cell Proliferation
Enzyme Activation
Gluconates
/ metabolism
Glucosephosphate Dehydrogenase
/ genetics
HEK293 Cells
HT29 Cells
Humans
K562 Cells
MCF-7 Cells
Mice, Nude
Neoplasms
/ enzymology
PC-3 Cells
Pentose Phosphate Pathway
Protein Binding
Protein Phosphatase 2
/ genetics
Protein Serine-Threonine Kinases
/ metabolism
Reactive Oxygen Species
/ metabolism
Ribulosephosphates
/ metabolism
Signal Transduction
Superoxide Dismutase
/ genetics
Tumor Burden
src-Family Kinases
/ metabolism
▪▪▪
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
19 12 2019
19 12 2019
Historique:
received:
15
04
2018
revised:
15
05
2019
accepted:
04
09
2019
pubmed:
7
10
2019
medline:
20
2
2020
entrez:
7
10
2019
Statut:
ppublish
Résumé
The oxidative pentose phosphate pathway (oxiPPP) contributes to cell metabolism through not only the production of metabolic intermediates and reductive NADPH but also inhibition of LKB1-AMPK signaling by ribulose-5-phosphate (Ru-5-P), the product of the third oxiPPP enzyme 6-phosphogluconate dehydrogenase (6PGD). However, we found that knockdown of glucose-6-phosphate dehydrogenase (G6PD), the first oxiPPP enzyme, did not affect AMPK activation despite decreased Ru-5-P and subsequent LKB1 activation, due to enhanced activity of PP2A, the upstream phosphatase of AMPK. In contrast, knockdown of 6PGD or 6-phosphogluconolactonase (PGLS), the second oxiPPP enzyme, reduced PP2A activity. Mechanistically, knockdown of G6PD or PGLS decreased or increased 6-phosphogluconolactone level, respectively, which enhanced the inhibitory phosphorylation of PP2A by Src. Furthermore, γ-6-phosphogluconolactone, an oxiPPP byproduct with unknown function generated through intramolecular rearrangement of δ-6-phosphogluconolactone, the only substrate of PGLS, bound to Src and enhanced PP2A recruitment. Together, oxiPPP regulates AMPK homeostasis by balancing the opposing LKB1 and PP2A.
Identifiants
pubmed: 31586547
pii: S1097-2765(19)30692-6
doi: 10.1016/j.molcel.2019.09.007
pmc: PMC6925637
mid: NIHMS1540008
pii:
doi:
Substances chimiques
6-phosphogluconolactone
0
Gluconates
0
Reactive Oxygen Species
0
Ribulosephosphates
0
ribulose 5-phosphate
4151-19-3
Glucosephosphate Dehydrogenase
EC 1.1.1.49
Superoxide Dismutase
EC 1.15.1.1
superoxide dismutase 2
EC 1.15.1.1
src-Family Kinases
EC 2.7.10.2
Protein Serine-Threonine Kinases
EC 2.7.11.1
STK11 protein, human
EC 2.7.11.1
AMP-Activated Protein Kinase Kinases
EC 2.7.11.3
AMP-Activated Protein Kinases
EC 2.7.11.31
Protein Phosphatase 2
EC 3.1.3.16
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
857-871.e9Subventions
Organisme : NIBIB NIH HHS
ID : T32 EB009380
Pays : United States
Organisme : NHGRI NIH HHS
ID : K01 HG006699
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA174786
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA140515
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA183594
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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