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Functional Characterization of Histidine Domain-Protein Tyrosine Phosphatase (HD-PTP) in Tumor Development

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Functional Characterization of Histidine Domain-Protein Tyrosine Phosphatase (HD-PTP) in Tumor Development Functional characterization of histidine domain-protein tyrosine phosphatase (HD-PTP) in tumor development By Sanaz Manteghi A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy Department of Biochemistry McGill University Montreal, QC, Canada December 2015 © Sanaz Manteghi, 2015 1 Abstract Histidine Domain containing Protein Tyrosine Phosphatase (HD-PTP/PTPN23) is part of the ESCRT (Endosomal Sorting Complex Required for Transport) complex with previously established function in cell surface receptor sorting, signaling and multi-vesicular body biogenesis. HD-PTP is encoded by the PTPN23 gene, which maps to chromosomal region 3p21.3, reported to be frequently deleted in various human cancers. However, the bona fide tumor suppressive role of HD-PTP has not been demonstrated yet. In this study we have investigated Ptpn23’s tumor suppressor function in vivo and we further assessed its role in cellular transformation and NF-κB pathway modulation in vitro. Components of the ESCRT complex have long been proposed to act as tumor suppressors. Here we show for the first time that PTPN23/HD-PTP, an ESCRT associated protein, exhibits tumor suppressor function in vivo. Ptpn23 hemizygous knockout mice are susceptible to the development of spontaneous B-cell lymphoma and lung adenocarcinoma. Moreover, B-cell lymphoma onset and dissemination were significantly potentiated by hemizygous loss of Ptpn23 in the transgenic Eµ-myc mouse model. Tumors derived from the Ptpn23+/- mice maintained HD- PTP expression and exhibited impaired apoptosis together with reduced levels of the ARF tumor suppressor. In addition, PTPN23 hemizygous loss resulted in partial cell transformation and increased migration/invasion. Furthermore, analysis of human cancer gene expression data revealed that heterozygous loss of PTPN23 is common in many human cancers, which is correlated with poor survival. This suggests that PTPN23/HD-PTP is a prominent tumor suppressor gene in human malignancies. Moreover, we identified a new function for HD-PTP in TNFα-induced canonical NF-κB activation downstream of TNFR1 receptor. We have shown that HD-PTP depleted cells have 2 increased cell surface TNFR1 and increased TNFR1 signaling complex formation which occurs due to defect in TNFR1 degradation in the context of HD-PTP deficiency. Furthermore, we have identified HD-PTP as a negative regulator of NF-κB pathway via TNFR1 receptor. We have shown that HD-PTP depleted cells display faster kinetics of NF-κB activation, increased target gene expression and inflammatory cytokine secretion upon TNFα stimulation. This suggests that HD- PTP inhibits NF-κB activation by controlling cell surface TNFR1 levels and recruitment of adaptor molecules to TNFR1 in order to attenuate the signaling cascade. In conclusion, these data suggest that PTPN23 is a haplo-insufficient tumor suppressor gene involved in tumor initiation, progression and NF-κB signaling, demonstrating for the first time the importance of an ESCRT component, HD-PTP, in tumorigenesis and immunity. Further investigation is required to determine the exact molecular mechanism of HD-PTP in tumorigenesis, inflammation and cancer. 3 Résumé La proteine Histidine Domain containing Protein Tyrosine Phosphatase (HD-PTP) fait partie du complexe ESCRT (Endosomal Sorting Complex Required for Transport), un complexe multiprotéique responsable du triage endosomal des récepteurs cellulaires de surface, ainsi que de la signalisation et de la formation des endosomes multi-vésiculaires (MVBs). La protéine HD-PTP est le produit du gène PTPN23, localisé dans la région chromosomale 3p21.3, une région fréquemment perdue dans plusieurs types de cancers humains. Néanmoins, la fonction suppresseur de tumeurs de HD-PTP n’a jamais été démontrée. Cette étude évalue la fonction suppresseur de tumeurs de HD-PTP in vivo, ainsi que le rôle de HD-PTP dans la transformation cellulaire et dans la régulation de la voie de signalisation NF-κB. Il a été précédemment suggéré que les constituants du complexe ESCRT agissent comme suppresseurs de tumeurs. Dans cette étude, nous démontrons pour la première fois la fonction suppresseur de tumeur de HD-PTP, une protéine associée avec la machinerie ESCRT. En effet, les souris hémizygotes pour Ptpn23 sont susceptibles au développement spontané de lymphomes à cellules B et d’adénocarcinomes pulmonaires. De plus, la perte d’une allèle de Ptpn23 potentialise significativement l’apparition et la dissémination de lymphomes induits dans le modèle transgénique murin exprimant l’oncogène Myc (Eμ-Myc). Les tumeurs dérivées des souris Ptpn23+/- préservent l’expression hémizygote de HD-PTP et démontrent des niveaux réduits d’apoptose et d’expression du suppresseur de tumeurs ARF. De plus, la déficience hémizygote de Ptpn23 induit la transformation partielle des cellules et augmente le phénotype pro-migratoire et pro-invasif de celles-ci. L’analyse de données d’expression génique de cancers humains révèle que la perte partielle de l’expression de PTPN23 est fréquente dans plusieurs types de tumeurs humaines et corrèle avec un mauvais pronostic. 4 Par ailleurs, nous avons identifié une nouvelle fonction de HD-PTP dans la régulation de la voie de signalisation canonique de NF-κB suite à une stimulation du récepteur TNFR1 avec TNFα. Nous avons démontré que les cellules déficientes pour HD-PTP ont des niveaux élevés de TNFR1 à la surface membranaire et une formation accrue de complexe de signalisation recruté subséquemment. Ces effets sont dus à une diminution de la dégradation de TNFR1 lorsque l’expression de HD-PTP est supprimée. Collectivement, ces effets mènent à une activation plus rapide de NF-κB et de l’expression de gènes spécifiques à cette cascade de signalisation, ainsi que l’augmentation de la sécrétion de cytokines pro-inflammatoires suite à une stimulation avec le TNFα. Nos résultats suggèrent que HD-PTP agit comme un inhibiteur de la voie de signalisation de NF-κB en modulant les niveaux d’expression de TNFR1 à la surface cellulaire et en régulant l’assemblement du complexe de signalisation afin d’atténuer la signalisation en aval. En résumé, nos résultats suggèrent fortement que Ptpn23 est un suppresseur de tumeurs haplo-insuffisant impliqué dans l’initiation de tumeurs, dans leur progression et dans la voie de signalisation NF-κB. Ces observations confirment pour la première fois le rôle suppresseur de tumeurs d’une composante de la machinerie ESCRT. Des études supplémentaires seront nécessaires afin d’élucider le mécanisme moléculaire précis de HD-PTP régulant l’inflammation et le cancer. 5 Acknowledgements I would like to thank My supervisor Dr. Arnim Pause who directed my training with continual guidance, and patience and for giving me the opportunity to work on a very challenging project. Present and former members of my research advisory committee, Dr. Jerry Pelletier, Dr. Maya Saleh, Dr. Russell Jones and Dr. Gerardo Ferbeyre for their valuable advice, critical comments and encouragement. My best colleague Dmitri Kharitidi, for being such an excellent person to work with on a daily basis during the last 5 years. My present and former labmates, Elena Malitskaya, Jin Yong Patrick Park, Luc Galarneau, Mikhail Chetcherbinine, Debora Cote, Anders Dydensborg, Yann Nouet, Ming Yan, Zahra Jalali, Mathieu Paquette, Tarika Vijayaraghavan, Sanket Khan, Elite Possik, (their contributions are listed in each chapter). Dr. Marie-Claude Gingras who initially started HD-PTP mouse model and for her help and assistance in this project. Dr. Marilène Paquet for performing pathology analysis. Dr. Regina Cencic and Dr. Francis Robert from Dr. Pelletier lab for their help with mouse experiments. Dr. Maud Marques from Dr. Michael Witcher’s lab, who kindly taught me to perform bioinformatic analysis of TCGA data. Dr. Maya Poffenberger and Eric Ma for performing IL6 ELISA assays. Dr. John R. Mills and Dr. Abba Malina for the insightful discussions on myc project. 6 Jin Yong Patrick Park, Anisa Domi, Takla Gris and Said Izreig for their help with editing of different chapters of this thesis. My family and my friends who are always there to help me through good and bad times and for their endless support, and encouraging words to keep me on track. Funding: Supported by a McGill Integrated Cancer Research Training Program (MICRTP) studentship award, a Canderel studentship award, a George G. Harris fellowship award in cancer, a McGill Biochemistry Graduate Excellence Fellowship award, and grants from the Cancer Research Society (CRS), the Canadian Cancer Society Research Institute (CCSRI: #700525 and #702500 to AP) and the McGill Collaborative Research and Development Fund. 7 Preface This thesis is written in manuscript format and resulted in one published review paper, two papers under revision and two papers in collaboration, one published and one under preparation for submission. 1. Dmitri Kharitidi*, Sanaz Manteghi* and Arnim Pause, Pseudo phosphatases: identification methods and physiological significance, Methods, S1046-2023(13)00378-2, (2013). (*Equally contributed) 2. Sanaz Manteghi, Marie-Claude Gingras, Dmitri Kharitidi, Luc Galarneau, Maud Marques, Ming Yan, Regina Cencic, Francis Robert, Marilène Paquet, Michael Witcher, Jerry Pelletier and Arnim Pause, Haploinsufficiency of the ESCRT component HD-PTP predisposes to cancer (in revision at Cell Reports) 3. Sanaz Manteghi*, Dmitri Kharitidi*, Jin Yong Patrick Park, Mikhail Chetcherbinine, Maya Poffenberger,
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