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Phosphatase Regulation by the Ovarian Oncoprotein URI1

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Phosphatase Regulation by the Ovarian Oncoprotein URI1 Research Collection Doctoral Thesis Phosphatase regulation by the ovarian oncoprotein URI1 Author(s): Jonasch, Helene Publication Date: 2015 Permanent Link: https://doi.org/10.3929/ethz-a-010399708 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH NO. 22593 Phosphatase regulation by the ovarian oncoprotein URI1 A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZURICH (Dr. sc. ETH Zurich) presented by HELENE JONASCH M.Sc. in Pharmaceutical Sciences, University of Basel born on 21.07.1987 citizen of Austria accepted on the recommendation of Prof. Dr. Wilhelm Krek Prof. Dr. Ian Frew Prof. Dr. med. Holger Moch 2015 Abstract URI1 encodes an unconventional member of the prefoldin family of molecular chaperones that is amplified in a variety of carcinomas including small-cell lung, gastric, breast, and ovarian cancer. Exisiting evidence suggests that the excessive production of URI1 in URI1-amplifed cancer cells fuels evasion from apoptosis. In this setting, mitochondria-localized URI1 detains phosphatase 1 gamma (PP1γ) in inactive complexes thereby sustains S6 kinase 1 (S6K1) survival signaling under conditions of nutrient and/or growth factor deprivation stress. These data suggest that in URI1-amplified cancers such as ovarian cancer, URI1 has properties of an addicting oncogene. To unveil potential novel URI1 oncoprotein functions at mitochondria, we embarked on the identification of URI1-associated mitochondrial proteins. We found the protein phosphatase 1 alpha (PP1α) to assembly into heterotrimeric complexes with URI1 and PP1γ to regulate URI1 phosphorylation alone or in collaboration with PP1γ in a cell type-specific manner. Moreover, we collected evidence suggesting that PP1α/PP1γ and the mammalian target of rapamycin (mTOR)/S6K1 axis oppose each other to dynamically regulate URI1 phophorylation state. Most strinkingly, we identified several proteins of the mitochondrial quality control machinery including the Parkin receptor mitofusin 2 (Mfn2) and the atypical protein phosphatase phosphoglycerate mutase family member 5 (PGAM5). The latter is known to undergo presenilin- associated rhomboid-like protein (PARL)-mediated cleavage and cytoplasmic translocation upon mitochondrial membrane potential dissipation. The processed form PGAM5(Δ24) carries a neo- inhibitor of apoptosis protein (IAP) binding motif enabling IAP antagonism and activation of caspases which sensitizes cells to apoptosis in response to mitochondrial damage. Intriguingly, we identified URI1 to be a major regulator of PGAM5 function by preventing PGAM5(Δ24) generation and translocation to the cytoplasm in ovarian cancer cells. By detaining PGAM5(Δ24) at mitochondria in the presence of the mitochondrial ionophore carbonyl cyanide 3-chlorophenylhydrazone (CCCP), URI1 protects cells from mitochondrial damage stress-induced apoptosis. Consistent with this view, depletion of URI1 renders ovarian cancer cells hypersensitive to CCCP-induced apoptosis in a caspase- and PGAM5-dependent manner. Notably, this protective function of URI1 in mitochondrial stress-induced apoptosis is independent of URI1 amplification status suggesting that URI1 not only acts as an addicting oncogene in ovarian cancer but may additionally display non-oncogene addiction features in the context of mitochondrial stress. Finally, we found that URI1 may further prevent apoptotic signaling by selective autophagic removal of damaged mitochondria mediated by the PTEN- putative kinase 1 (PINK1)/Parkin pathway. We identified URI1 to be required for Parkin self- degradation and its mitochondrial translocation upon mitophagy induction in URI1-amplified OVCAR-8 cells. Together, we propose a novel function of URI1 in the regulation of mitochondrial stress-induced apoptosis in ovarian cancer cells. 2 Zusammenfassung URI1 kodiert ein unkonventionelles Mitglied der Prefoldin Familie der molekularen Chaperone, dass in einer Vielzahl von Karzinomen, wie zum Beispiel kleinzelligem Lungen-, Magen-, Brust- und Ovarialkrebs amplifiziert ist. Die vorliegenden Erkenntnisse weisen darauf hin, dass die exzessive Produktion von URI1 in URI1-amplifizierten Krebszellen das Umgehen der Apoptose fördert. In diesem Rahmen hält mitochondrial lokalisiertes URI1 die Protein Phosphatase 1 gamma (PP1γ) in inaktiven Komplexen und erhält dadurch den S6 Kinase 1 (S6K1) Überlebens-Signalweg unter selbst unter Stresskonditionen, die durch Nährstoff- und Wachstumsfakormangel ausgelöst werden. Diese Daten weisen darauf hin, dass URI1 in URI1-amplifizierten Krebsarten wie Ovarialkrebs Eigenschaften eines Abhängigkeits vermittelnden Onkogens hat. Um potentiell neue URI1 Onkoprotein Funktionen an den Mitochondrien zu enthüllen, haben wir mit der Identifizierung von URI1-assoziierten mitochondrialen Proteinen begonnen. Wir fanden, dass die Protein Phosphatase 1 alpha heterotrimere Komplexe mit URI1 und PP1γ bildet um die Phosphorylierung von URI1 alleine oder in Kollaboration mit PP1γ in einer Zelltyp spezifischen Weise zu regulieren. Unsere Daten weisen darauf hin, dass sich PP1α/PP1γ und die mTOR (Ziel des Rapamycins im Säugetier)/S6K1 Achse gegenüberstehen, um den Phosphorylierungsstatus von URI1 dynamisch zu kontrollieren. Am bemerkenswertesten war unsere Identifizierung mehrerer Proteine der mitochondrialen Qualitätskontrollmaschinerie einschliesslich des Parkin-Rezeptors Mitofusin 2 (Mfn2) und der atypischen Phosphatase Phosphoglycerate Mutase Familien Mitglied 5 (PGAM5). PGAM5 wird bei der Zerstörung des mitochondrialen Membranpotentials durch PARL (Präsenilin-assoziiertes Rhomboid-ähnliches Protein) gespalten und die gespaltene Form ins Zytoplasma transportiert. Die prozessierte Form PGAM5(Δ24) trägt ein Neo-Inhibitor der Apoptose Proteine (IAP) Bindungsmotif, das IAP antagonisiert und die Aktivierung von Caspasen ermöglicht, was die Zellen als Reaktion auf mitochondriale Schädigung für Apoptose sensibilisiert. Bemerkenswerterweise haben wir URI1 als wesentlichen Regulator der PGAM5 Funktion identifiziert, indem es in Ovarialkrebszellen die Generierung von PGAM5(Δ24) und dessen Translokation ins Zytoplasma verhindert. Durch Zurückhalten von PGAM5(Δ24) an dem Mitochondrien in der Anwesenheit des mitochondrialen Ionophors Carbonyl Cyanide 3-Chlorophenylhydrazone (CCCP) schützt URI1 vor Apoptose, die durch Beschädigung der Mitochondrien ausgelöst wird. Dementsprechend führt URI1 Knockdown in Ovarialkrebszellen zu einer Hypersensitivität gegenüber CCCP-induzierter Apoptose in einer Caspase- und PGAM5-abhängigen Weise. Bemerkenswerterweise ist diese beschützende Funktion von URI1 in mitochondrialer Stress induzierter Apoptose unabhängig vom URI1 Amplifikationsstatus. Dies weist darauf hin, dass URI1 nicht nur als ein Abhängigkeits vermittelndes Onkogen in Ovarialkrebs agiert, sondern möglicherweise zusätzliche Eigenschaften einer nicht-onkogenen Abhängigkeit in Kontext des mitochondrialen Stresses zeigt. Letztlich haben wir gefunden, dass URI1 möglicherweise durch 3 selektives autophagisches Entfernen der beschädigten Mitochondrien, ausgeführt durch die PTEN- putative Kinase 1 (PINK1)/Parkin Signalkaskade, apoptotische Signalwege weiter verhindert. Wir stellten fest, dass in URI1-amplifizierten OVCAR-8 Zellen URI1 erforderlich ist für die Parkin Selbstdegradation und dessen mitochondriale Translokation durch Mitophagie-Induktion. Zusammenfassend schlagen wir eine neuartige Funktion von URI1 in der Regulation von mitochondrialer Stress induzierter Apoptose in Ovarialkrebszellen vor. 4 Acknowledgments I would like to express my gratitude to Prof. Dr. Wilhelm Krek for giving me the opportunity to work in his laboratory and to discover the field of cancer biology with great scientific freedom. I am deeply grateful for his valuable advice, his enthusiasm, and the chance to continue my project after the doctoral defense. I would like to show my gratitude to my thesis committee, Prof. Dr. Ian Frew and Prof. Dr. med. Holger Moch, for very constructive discussions and helpful advice. Special thanks go to Dr. Karen Schrader, who supervised me during the first months and supported me anytime with her friendly advice. I would like to thank Dr. Matthias Gstaiger and especially Dr. Simon Hauri for competent advice and his excellent work during the mass spectrometry analysis. I thank Lukas Frischknecht for great discussions and sharing PGAM5 tools, in particular I would like to thank him for generating the PGAM5 antibody. I am grateful to the past and present lab members for their great help and support. Especially, I thank Dr. Dr. Christian Britschgi and Dr. Stefan Metzler for sharing their deep knowledge as well as my lab mates from H21.2 for cheerful hours in the laboratory. Special thanks also go to Rebekka Stark for her great willingness to help me with cell culture work. I would like to say thank you to Dr. Rafal Pawlowski and Dr. Werner Kovacs, who took the time to correct and improve my thesis. I would like to thank Prof. Dr. Viola Heinzelmann-Schwarz for providing me with the HOSE cell lines. I would like to show my gratitude to Dr. Rico Funhoff and Dr. Axel Vicart, who promoted my scientific development and encouraged me to become a Ph.D. student. I would like to send my thanks out to Dr. Ruth Leu Marseiler who has accompanied me on my carrier for several years already with her valuable advice. I would like to express my warmest thanks to
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