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Cancer Res. 2018 Dec 1;78(23):6539-6548. doi: 10.1158/0008-5472.CAN-18-0901. Epub 2018 Oct 8.

Pathologic Oxidation of PTPN12 Underlies ABL1 Phosphorylation in Hereditary Leiomyomatosis and Renal Cell Carcinoma.

Author information

1
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
2
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
3
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York.
4
SPARC BioCentre and Program in Cell Biology, Hospital for Sick Children, Canada.
5
Proteomics Laboratory, Division of Advanced Research and Technology, NYU Langone Health, New York, New York.
6
Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York, New York.
7
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut.
8
Department of Molecular Genetics, University of Toronto, Canada.
9
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
10
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. benjamin.neel@nyumc.org.

Abstract

: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an inherited cancer syndrome associated with a highly aggressive form of type 2 papillary renal cell carcinoma (PRCC). Germline 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 activation of ABL1, which promotes tumor growth, but how ABL1 is activated remains unclear. Given that oxidation can regulate protein-tyrosine phosphatase (PTP) catalytic activity, inactivation of an ABL-directed PTP by ROS might account for ABL1 activation in this malignancy. Our group previously developed "q-oxPTPome," a method that globally monitors the oxidation of classical PTPs. In this study, we present a refined q-oxPTPome, increasing its sensitivity by >10×. Applying q-oxPTPome to FH-deficient cell models showed that multiple PTPs were either highly oxidized (including PTPN12) or overexpressed. Highly oxidized PTPs were those with relatively high sensitivity to exogenous H2O2. Most PTP oxidation in FH-deficient cells was reversible, although nearly 40% of PTPN13 was irreversibly oxidized 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 identified PTPN12 as the major ABL1 phosphatase, and overexpression of PTPN12 inhibited ABL1 phosphorylation and HLRCC cell growth. These results show that ROS-induced oxidation of PTPN12 accounts for ABL1 phosphorylation in HLRCC-associated PRCC, revealing a novel mechanism for inactivating a tumor suppressor gene product and establishing a direct link between pathologic PTP oxidation and neoplastic disease. SIGNIFICANCE: This work identifies a novel mechanism of activation of the oncogenic kinase ABL1 via ROS-induced, oxidation-mediated inactivation of cognate protein tyrosine phosphatases.

PMID:
30297534
PMCID:
PMC6279512
[Available on 2019-12-01]
DOI:
10.1158/0008-5472.CAN-18-0901

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