Send to

Choose Destination
Nat Cell Biol. 2016 Jul;18(7):803-813. doi: 10.1038/ncb3376. Epub 2016 Jun 20.

PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia.

Author information

Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
Department of Genetics, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, M5S 3E1, Canada.
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York University, New York, NY 10016, USA.
Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Radiation System Biology, Institute of Radiation Biology Center, Kyoto University, Kyoto, Japan.
Chemistry Research Laboratory, Oxford University, 12 Mansfield Road, Oxford OX1 3TA, UK.
Contributed equally


Tumours exist in a hypoxic microenvironment and must limit excessive oxygen consumption. Hypoxia-inducible factor (HIF) controls mitochondrial oxygen consumption, but how/if tumours regulate non-mitochondrial oxygen consumption (NMOC) is unknown. Protein-tyrosine phosphatase-1B (PTP1B) is required for Her2/Neu-driven breast cancer (BC) in mice, although the underlying mechanism and human relevance remain unclear. We found that PTP1B-deficient HER2(+) xenografts have increased hypoxia, necrosis and impaired growth. In vitro, PTP1B deficiency sensitizes HER2(+) BC lines to hypoxia by increasing NMOC by α-KG-dependent dioxygenases (α-KGDDs). The moyamoya disease gene product RNF213, an E3 ligase, is negatively regulated by PTP1B in HER2(+) BC cells. RNF213 knockdown reverses the effects of PTP1B deficiency on α-KGDDs, NMOC and hypoxia-induced death of HER2(+) BC cells, and partially restores tumorigenicity. We conclude that PTP1B acts via RNF213 to suppress α-KGDD activity and NMOC. This PTP1B/RNF213/α-KGDD pathway is critical for survival of HER2(+) BC, and possibly other malignancies, in the hypoxic tumour microenvironment.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center