Rxivist logo

Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 54,982 bioRxiv papers from 253,713 authors.

Pathological Oxidation of PTPN12 Underlies ABL1 Phosphorylation in HLRCC

By Yang Xu, Paul Taylor, Joshua Andrade, Beatrix Ueberheide, Brian Shuch, Peter M Glazer, Ranjit S Bindra, Michael F Moran, Marston Linehan, Benjamin G Neel

Posted 06 Apr 2018
bioRxiv DOI: 10.1101/296194

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an inherited cancer syndrome associated with a highly aggressive form of type 2 papillary renal cell carcinoma (PRCC). Germ line inactivating alterations in Fumarate Hydratase (FH) cause HLRCC, and result in elevated levels of reactive oxygen species (ROS). Recent work indicates that FH -/- PRCC cells have increased ABL1 activation, which promotes tumor growth, but how ABL1 is activated remained unclear. Oxidation can regulate protein-tyrosine phosphatase (PTP) catalytic activity; conceivably, ROS-catalyzed inactivation of an ABL-directed PTP might account for ABL1 activation in this malignancy. Previously, our group developed q-oxPTPome, a method that can globally monitor the oxidation of classical PTPs. We have now refined the q-oxPTPome approach, increasing its sensitivity by >10X. Applying q-oxPTPome to FH-deficient cell models shows that multiple PTPs are either highly oxidized (including PTPN12) or overexpressed. In general, highly oxidized PTPs were those that have relatively high sensitivity to exogenous H2O2. Most PTP oxidation in FH-deficient cells is reversible, although nearly 40% of PTPN13 is oxidized irreversibly to the sulfonic acid state. Using substrate-trapping mutants, we mapped PTPs to their putative substrates, and found that only PTPN12 could target ABL1. Furthermore, knockdown experiments identify PTPN12 as the major ABL1 phosphatase in HLRCC. Overall, our results show that ROS-induced PTPN12 oxidation accounts for ABL1 phosphorylation in HLRCC-associated PRCC, reveal a novel mechanism for inactivating a tumor suppressor gene product, and establish a direct link between pathological PTP oxidation and neoplastic disease.

Download data

  • Downloaded 151 times
  • Download rankings, all-time:
    • Site-wide: 41,909 out of 54,982
    • In cancer biology: 1,318 out of 1,771
  • Year to date:
    • Site-wide: 45,014 out of 54,982
  • Since beginning of last month:
    • Site-wide: 26,804 out of 54,982

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide

Sign up for the Rxivist weekly newsletter! (Click here for more details.)