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PMID:21074248

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Citation

Fang, M, Shen, Z, Huang, S, Zhao, L, Chen, S, Mak, TW and Wang, X (2010) The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell 143:711-24

Abstract

PI3K and PTEN lipid phosphatase control the level of cellular phosphatidylinositol (3,4,5)-trisphosphate, an activator of AKT kinases that promotes cell growth and survival. Mutations activating AKT are commonly observed in human cancers. We report here that ENTPD5, an endoplasmic reticulum (ER) enzyme, is upregulated in cell lines and primary human tumor samples with active AKT. ENTPD5 hydrolyzes UDP to UMP to promote protein N-glycosylation and folding in ER. Knockdown of ENTPD5 in PTEN null cells causes ER stress and loss of growth factor receptors. ENTPD5, together with cytidine monophosphate kinase-1 and adenylate kinase-1, constitute an ATP hydrolysis cycle that converts ATP to AMP, resulting in a compensatory increase in aerobic glycolysis known as the Warburg effect. The growth of PTEN null cells is inhibited both in vitro and in mouse xenograft tumor models. ENTPD5 is therefore an integral part of the PI3K/PTEN regulatory loop and a potential target for anticancer therapy.

Links

PubMed Online version:10.1016/j.cell.2010.10.010

Keywords

5'-Guanylic Acid/metabolism; Adenosine Triphosphate/metabolism; Aerobiosis; Animals; Cell Line, Tumor; Cell Proliferation; Endoplasmic Reticulum/metabolism; Glycolysis; Glycosylation; Humans; Mice; Neoplasm Transplantation; Oncogene Protein v-akt/metabolism; Oncogene Proteins/genetics; Oncogene Proteins/metabolism; PTEN Phosphohydrolase/genetics; PTEN Phosphohydrolase/metabolism; Pyrophosphatases; Transplantation, Heterologous; Uridine Monophosphate/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ENTP5

located_in

GO:0005783: endoplasmic reticulum

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ENTP5

involved_in

GO:0014066: regulation of phosphatidylinositol 3-kinase signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ENTP5

enables

GO:0004382: guanosine-diphosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:ENTP5

involved_in

GO:0006487: protein N-linked glycosylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ENTP5

enables

GO:0045134: uridine-diphosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:ENTP5

involved_in

GO:0051084: 'de novo' posttranslational protein folding

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ENTP5

involved_in

GO:0046034: ATP metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ENTP5

involved_in

GO:0045821: positive regulation of glycolytic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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