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

Abstract

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.

• Authors: Robert S Banh, Caterina Iorio, Richard Marcotte, Yang Xu, Dan Cojocari, Anas Abdel Rahman, Judy Pawling, Wei Zhang, Ankit Sinha, Christopher M Rose, Marta Isasa, Shuang Zhang, Ronald Wu, Carl Virtanen, Toshiaki Hitomi, Toshiyuki Habu, Sachdev S Sidhu, Akio Koizumi, Sarah E Wilkins, Thomas Kislinger, Steven P Gygi, Christopher J Schofield, James W Dennis, Bradly G Wouters, Benjamin G Neel
• Journal: Nature cell biology (Nat Cell Biol) Vol. 18 Issue 7 Pg. 803-813 (07 2016) ISSN: 1476-4679 [Electronic] England
• PMID: 27323329 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Alpha-Ketoglutarate-Dependent Dioxygenase FTO
• RNF213 protein, human
• RNF213 protein, mouse
• Ubiquitin-Protein Ligases
• PTPN1 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Ptpn1 protein, mouse
• Adenosine Triphosphatases

Topics

• Adenosine Triphosphatases (metabolism)
• Alpha-Ketoglutarate-Dependent Dioxygenase FTO (metabolism)
• Animals
• Breast Neoplasms (metabolism)
• Cell Hypoxia
• Female
• Genes, erbB-2 (genetics)
• Humans
• Mice
• Mitochondria (metabolism)
• Oxygen Consumption (physiology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (metabolism)
• Ubiquitin-Protein Ligases (metabolism)