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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 ?-KG-dependent dioxygenases (?-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 ?-KGDDs, NMOC and hypoxia-induced death of HER2(+) BC cells, and partially restores tumorigenicity. We conclude that PTP1B acts via RNF213 to suppress ?-KGDD activity and NMOC. This PTP1B/RNF213/?-KGDD pathway is critical for survival of HER2(+) BC, and possibly other malignancies, in the hypoxic tumour microenvironment.

SUBMITTER: Banh RS

PROVIDER: S-EPMC4936519 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Banh Robert S RS Iorio Caterina C Marcotte Richard R Xu Yang Y Cojocari Dan D Rahman Anas Abdel AA Pawling Judy J Zhang Wei W Sinha Ankit A Rose Christopher M CM Isasa Marta M Zhang Shuang S Wu Ronald R Virtanen Carl C Hitomi Toshiaki T Habu Toshiyuki T Sidhu Sachdev S SS Koizumi Akio A Wilkins Sarah E SE Kislinger Thomas T Gygi Steven P SP Schofield Christopher J CJ Dennis James W JW Wouters Bradly G BG Neel Benjamin G BG

Nature cell biology 20160620 7

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 a ...[more]

PMID: 27323329

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Project description:Oxygen levels in cancerous tissue can have a significant effect on treatment response: hypoxic tissue is both more radioresistant and more chemoresistant than well-oxygenated tissue. While recent advances in medical imaging have facilitated real-time observation of macroscopic oxygenation, the underlying physics limits the resolution to the millimetre domain, whereas oxygen tension varies over a micrometre scale. If the distribution of oxygen in the tumour micro-environment can be accurately estimated, then the effect of potential dose escalation to these hypoxic regions could be better modelled, allowing more realistic simulation of biologically adaptive treatments. Reaction-diffusion models are commonly used for modelling oxygen dynamics, with a variety of functional forms assumed for the dependence of oxygen consumption rate (OCR) on cellular status and local oxygen availability. In this work, we examine reaction-diffusion models of oxygen consumption in spherically and cylindrically symmetric geometries. We consider two different descriptions of oxygen consumption: one in which the rate of consumption is constant and one in which it varies with oxygen tension in a hyperbolic manner. In each case, we derive analytic approximations to the steady-state oxygen distribution, which are shown to closely match the numerical solutions of the equations and accurately predict the extent to which oxygen can diffuse. The derived expressions relate the limit to which oxygen can diffuse into a tissue to the OCR of that tissue. We also demonstrate that differences between these functional forms are likely to be negligible within the range of literature estimates of the hyperbolic oxygen constant, suggesting that the constant consumption rate approximation suffices for modelling oxygen dynamics for most values of OCR. These approximations also allow the rapid identification of situations where hyperbolic consumption forms can result in significant differences from constant consumption rate models, and so can reduce the computational workload associated with numerical solutions, by estimating both the oxygen diffusion distances and resultant oxygen profile. Such analysis may be useful for parameter fitting in large imaging datasets and histological sections, and allows easy quantification of projected differences between functional forms of OCR.

Project description:The tumor microenvironment (TME) typically includes hypoxic regions. Hypoxic cancer cells are resistant to many anti-neoplastic therapies and can seed recurrence; consequently, understanding how they survive could yield new therapeutic strategies. In response to decreasing oxygen, cells are known to successively activate hypoxia-inducible factor 1-alpha (HIF1alpha), endoplasmic reticulum (ER) stress, and AMP-dependent protein kinase (AMPK). We previously identified an additional pathway in which the protein-tyrosine phosphatase PTP1B (encoded by PTPN1) prevents the death of HER2+ breast cancer cells exposed to severe hypoxia (O2<1%) by inhibiting RNF213, a large (~600 kDa) E3 ubiquitin ligase containing two functional AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) that also is implicated in Moyamoya disease (MMD), lipotoxicity, and innate immunity. These findings provided a potential explanation for earlier observations that Ptpn1-/- mice are resistant to Neu (rodent HER2)-induced breast cancer, but how PTP1B regulates RNF213, the identity(ies) of RNF213 targets, the mechanism of cell death, and the relevance to other RNF213 actions remained unclear. Via proximity-based proteomics, we identified the CYLD-SPATA2 complex, a major negative regulator of NF-kappaB activation, as an RNF213 substrate critical for hypoxia-induced cell death. Here we show that PTP1B and ABL1/2 reciprocally control the phosphorylation of RNF213 on Tyrosine-1275. Phosphorylation of this site promotes RNF213 oligomerization, resulting in RZ domain activation, LUBAC complex-dependent ubiquitylation and degradation of the CYLD/SPATA2 deubiquitinase complex, and NF-kappaB activation. NF-kappaB induces NLRP3 inflammasome priming, and concomitant hypoxia-induced ER stress triggers inflammasome activation, resulting in pyroptotic cell death. Mutagenesis experiments show that the RNF213 RING negatively regulates the RZ domain, and RING domain mutants, including those associated with MMD, catalyze LUBAC-independent CYLD/SPATA2 degradation. Our results identify a novel PTP1B/RNF213/CYLD/SPATA2 pathway responsible for the pyroptotic death of hypoxic tumor cells, reveal new insights into RNF213 regulation, and have potentially important implications for the pathogenesis of MMD, atherosclerosis, and inflammatory and auto-immune disorders. The mass spectrometry raw files for the phosphorylation identification and proximity labeling results are included here.

Dataset Information

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

Publications

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

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