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Pathologic Oxidation of PTPN12 Underlies ABL1 Phosphorylation In Published OnlineFirst October 8, 2018; DOI: 10.1158/0008-5472.CAN-18-0901 Cancer Priority Report Research Pathologic Oxidation of PTPN12 Underlies ABL1 Phosphorylation in Hereditary Leiomyomatosis and Renal Cell Carcinoma Yang Xu1,2,3, Paul Taylor4, Joshua Andrade5, Beatrix Ueberheide5,6, Brian Shuch7, Peter M. Glazer7, Ranjit S. Bindra7, Michael F. Moran4,8, W. Marston Linehan9, and Benjamin G. Neel1,2,3 Abstract Hereditary leiomyomatosis and renal cell carcinoma PTP oxidation in FH-deficient cells was reversible, although (HLRCC) is an inherited cancer syndrome associated with a nearly 40% of PTPN13 was irreversibly oxidized to the highly aggressive form of type 2 papillary renal cell carcinoma sulfonic acid state. Using substrate-trapping mutants, we (PRCC). Germline inactivating alterations in fumarate hydratase mapped PTPs to their putative substrates and found that (FH) cause HLRCC and result in elevated levels of reactive only PTPN12 could target ABL1. Furthermore, knockdown À À oxygen species (ROS). Recent work indicates that FH / PRCC experiments identified PTPN12 as the major ABL1 phos- cells have increased activation of ABL1, which promotes tumor phatase, and overexpression of PTPN12 inhibited ABL1 growth, but how ABL1 is activated remains unclear. Given that phosphorylation and HLRCC cell growth. These results oxidation can regulate protein-tyrosine phosphatase (PTP) show that ROS-induced oxidation of PTPN12 accounts for catalytic activity, inactivation of an ABL-directed PTP by ROS ABL1 phosphorylation in HLRCC-associated PRCC, reveal- might account for ABL1 activation in this malignancy. Our ing a novel mechanism for inactivating a tumor suppressor group previously developed "q-oxPTPome," a method that gene product and establishing a direct link between path- globally monitors the oxidation of classical PTPs. In this study, ologic PTP oxidation and neoplastic disease. we present a refined q-oxPTPome, increasing its sensitivity by >10Â. Applying q-oxPTPome to FH-deficient cell models Significance: This work identifies a novel mechanism of showed that multiple PTPs were either highly oxidized (includ- activation of the oncogenic kinase ABL1 via ROS-induced, ing PTPN12) or overexpressed. Highly oxidized PTPs were oxidation-mediated inactivation of cognate protein tyrosine those with relatively high sensitivity to exogenous H2O2. Most phosphatases. Cancer Res; 78(23); 6539–48. Ó2018 AACR. Introduction messengers in cellular signaling pathways (1). Protein-tyrosine phosphatases (PTP) are major ROS targets under physiologic and Reactive oxygen species (ROS), including superoxide anion > À * pathologic conditions. The PTP superfamily has 100 members, (O ), hydrogen peroxide (H O ), and hydroxyl radical ( OH), 2 2 2 including 38 classical PTPs, which specifically dephosphorylate are toxic by-products of aerobic respiration, but also act as second phosphotyrosine (2, 3). Classical PTPs comprise non-transmem- brane PTPs (NT-PTP) and receptor-like PTPs (R-PTP). Nearly all NT-PTPs have a single catalytic (PTP) domain, whereas most 1Department of Medical Biophysics, University of Toronto, Toronto, Ontario, R-PTPs have two PTP domains (D1, D2), with D1 typically Canada. 2Princess Margaret Cancer Centre, University Health Network, Toronto, harboring the catalytic activity and D2 having regulatory func- 3 Ontario, Canada. Laura and Isaac Perlmutter Cancer Center, New York Uni- tions. Classical PTPs are defined by a conserved signature motif versity Langone Medical Center, New York, New York. 4SPARC BioCentre and 5 (I/V)HCSAGXXR(S/T)G, containing an essential catalytic cystei- Program in Cell Biology, Hospital for Sick Children, Canada. Proteomics Lab- À oratory, Division of Advanced Research and Technology, NYU Langone Health, nyl residue that exists as a thiolate anion (S ) at physiologic pH New York, New York. 6Department of Biochemistry and Molecular Pharmacol- and is quite susceptible to oxidization. Upon exposure to ROS, the ogy, NYU Langone Health, New York, New York. 7Department of Therapeutic PTP thiolate can be oxidized to the sulfenic acid (S-OH) state, Radiology, Yale University School of Medicine, New Haven, Connecticut. which is labile and immediately rearranges to a disulfide (S-S) or 8 9 Department of Molecular Genetics, University of Toronto, Canada. Urologic sulfenylamide (S-N) bond. These events reversibly inhibit PTP Oncology Branch, Center for Cancer Research, National Cancer Institute, activity and protect the catalytic cysteine from irreversible oxida- Bethesda, Maryland. tion to the sulfinic (SO2H) or sulfonic (SO3H) acid. PTP oxidation Note: Supplementary data for this article are available at Cancer Research reportedly occurs in physiologic and pathologic cellular process- Online (http://cancerres.aacrjournals.org/). es, including growth factor signaling, cytokine signaling, integrin Corresponding Author: Benjamin G. Neel, New York University School of signaling, diabetes, atherosclerosis, chronic inflammation, and Medicine, 522 First Avenue, Smilow 12th Fl. Suite 1201, New York, NY 10016. cancer (4). Phone: 212-263-3019; Fax: 212-263-9190; E-mail: [email protected] Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) doi: 10.1158/0008-5472.CAN-18-0901 is an inherited syndrome, caused by germline inactivating altera- Ó2018 American Association for Cancer Research. tions in fumarate hydratase (FH), that places patients at risk of a www.aacrjournals.org 6539 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst October 8, 2018; DOI: 10.1158/0008-5472.CAN-18-0901 Xu et al. highly aggressive, poor prognosis form of type 2 papillary renal from R&D Systems; anti-ERK2 (D-2), anti-FH (H-6), anti-SHP2 cell carcinoma (PRCC; refs. 5–7). FH encodes a TCA cycle (C-18 and B1), and anti-ABL1 (8E9) antibodies from Santa enzyme (8), whose loss-of-function results in accumulation Cruz; anti-PSTPIP2 (HPA040944) and anti-Flag (M2) anti- of fumarate, which leads to inactivation of the antioxidant bodies from Sigma; anti-PTPN12 antibody (A700-007) from glutathione (GSH) and persistent oxidative stress (9, 10). Bethyl; anti-PSTPIP1 antibodies (ab197260) from Abcam; Consequently, HLRCC cells have elevated ROS levels, despite anti-phosphotyrosine antibodies (4G10) from Millipore; hyper-activation of the antioxidant protein NRF2 (11–13). A anti-pERK (9101), anti-ABL1 (2862), anti-pABL Y245 recent study demonstrated that FH deficiency-induced ROS (2861), anti-PTPN18 (8311), anti-pCRKL Y207 (3181), anti- indirectly stimulate ABL1 phosphorylation/activation, which, CRKL (3182), anti-pCRKII Y221 (3491), and anti-CRKII À À in turn, is critical for FH / PRCC growth and survival (14). (3492) antibodies from Cell Signaling Technology. siRNAs However, the precise mechanism by which ROS cause increased (SMARTpools or individual siRNAs) for PTPN12, PTPN18, ABL1 activation remained undefined. and ABL1 were from Dharmacon. We hypothesized that the increased ROS in HLRCC-associ- For immunoprecipitation, lysates (1–2mgprotein)were ated PRCC might induce oxidation and inactivation of the PTP incubated with anti-Flag M2 affinity gel (Sigma) overnight at that normally dephosphorylates ABL1. Several methods for 4C, washed 4Â in lysis buffer, resolved by SDS-PAGE and detecting PTP oxidation have been developed, including the analyzed by immunoblotting. in-gel PTPase assay, alkylating agent-based assays, dimedone- based assays, and specific antibodies against oxidized forms of q-oxPTPome PTPs (15). Nevertheless, identifying endogenously oxidized A buffer containing 20 mmol/L Tris (pH 7.35), 150 mmol/L cellular PTPs remains challenging. Previously, we developed NaCl, 10% glycerol, 1% NP40 was degassed overnight and then a mass spectrometry (MS)-based method, q-oxPTPome, which transferred to a hypoxia workstation (Don Whitley Scientific). can monitor the oxidation of all catalytically active classical Immediately before use, 30 mmol/L N-ethylmaleimide (NEM; PTPs (16). We substantially refined this protocol, combining it Sigma), 0.5 U/mL catalase (Calbiochem), 0.125 U/mL superoxide with filter-aided sample preparation (FASP; ref. 17), and dismutase (Sigma), and a protease inhibitor cocktail (2 mg/mL increased its sensitivity by at least 10-fold. Using this approach, antipain, 2 mg/mL pepstatin A, 20 mg/mL leupeptin, and 20 mg/mL we found that several PTPs were highly oxidized in FH-deficient aprotinin) were added to the lysis buffer. Within the work- PRCC cell lines, and identified PTPN12 oxidation as the cause station, cells were quickly washed once with degassed PBS, of increased ABL1 tyrosyl phosphorylation, establishing a novel immediately lysed, incubated for 1 hour at 4Cinthedarkwith mechanism of tumorigenesis. constant rotation, and clarified at 10,000 Â g for 1 minute at 4C. Supernatants were collected in the hypoxia workstation and buffer-exchanged by gel filtration (GE Healthcare) into Materials and Methods degassed solution [20 mmol/L HEPES (pH 7.4), 100 mmol/L Cell lines and cell culture NaCl, 10% glycerol, 0.05% NP40, 0.02 U/mL catalase]. Desalted HEK293 T-REx cells were obtained from ThermoFisher. HeLa lysates were treated with 5 mmol/L DTT and rotated in the dark T-REx cells (early passage) were kindly provided by Dr. Brian for 1.5 hours at 37C. Within the workstation, lysates were Raught (Princess Margaret Cancer Centre, Canada). UOK262 again buffer-exchanged to remove DTT, freshly prepared per- FH-WT, UOK262 FH-deficient, UOK268 FH-WT, and UOK268 vanadate was
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