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The Human G Protein-Coupled Receptor GPR30: Interaction Partners and Expression Analysis in Endothelial Cells

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The Human G Protein-Coupled Receptor GPR30: Interaction Partners and Expression Analysis in Endothelial Cells Center for Cardiovascular Research, Charité, Berlin & Max-Planck Institut for Molecular Genetics, Berlin The human G Protein-Coupled Receptor GPR30: interaction partners and expression analysis in endothelial cells Dissertation zur Erlangung des akademischen Grades doctor rerum naturalium (Dr. rer. Nat.) im Fach Biologie eingereicht an der Mathematisch-Naturwissenschaftlichen Fakultät I der Humboldt-Universität zu Berlin von Valeria Zazzu Präsident: Prof. Dr. Jan-Hendrik Olbertz Dekan: Prof. Dr. Andreas Herrmann Gutachter/innen: 1. Prof. Dr. Patricia Ruiz Noppinger 2. Prof. Dr. Peter-Michael Kloetzel 3. Prof. Dr. Franz Theuring Datum der mündl. Prüfung: 02.03.2011 Dedicata a Papà e Mamma ZUSAMMENFASSUNG Im Jahr 1997 wurden der Orphan-G-Protein-gekoppelte Rezeptor 30 (GPR30) aus menschlichen Nabelschnur-Endothelzellen (HUVECs) kloniert, die Fluid Shear Stress (FSS), einer mechanischen Kraft, die auf Blutgefäße wirkt, ausgesetzt waren. In dieser Studie von Takada et al konnte gezeigt werden, dass die Expression von GPR30 durch die FSS- Behandlung im Vergleich zu unbehandelten HUVEC-Zellen deutlich induziert wurde. Daraufhin wurde in einer Studie im dem Labor, in dem die Experimente für diese Arbeit durchgeführt wurden, die zelluläre und gewebsspezifische Expression von GPR30 in GPR30-LacZ Reportergen-Mäusen untersucht. Es konnte eine Expression von GPR30 vorwiegend in den Endothelzellen der kleinen Arterien verschiedenster Gewebetypen nachgewiesen werden. Vor einigen Jahren wurde von zwei unabhängigen Gruppen postuliert, dass GPR30, 17-β- Östradiol (E2) direkt binden kann und dadurch rasche nicht-genomische Signale vermittelt. Im Gegensatz dazu haben verschiedene andere Veröffentlichungen gezeigt, dass E2 nicht spezifisch an GPR30 bindet. Trotz der Kontroverse, ob es sich bei GPR30 um einen Östrogenrezeptor oder um einen Orphan-Rezeptor handelt, ist bislang nichts über seine Interaktion zu anderen Proteinen und deren Wechselwirkung bekannt. Deswegen, und aufgrund der Tatsache, dass mehrere Berichte darauf hindeuten, dass GPCRs mit mehreren Proteinen (neben denen, die in der traditionellen Vorstellung mit heterotrimeren G-Proteine wechselwirken) interagieren bzw. von diesen reguliert werden, war ein Ziel dieser Arbeit, Interaktionspartner von menschlichen GPR30 zu identifizieren und folglich ein humanes vaskuläres in vitro Modell zu etabliren, um die potentiellen Interaktionen von GPR30 sowie die downstream-Effekte der Wechselwirkung zwischen GPR30 und den neuen Interaktionspartner des vaskulären Modells auf Transkriptebene zu evaluieren. Ein Screening einer humanen kardiovaskulären cDNA-Bibliothek mit Hilfe des Hefe-2-Hybrid (Y2H)-Systems führte zur Identifizierung mehrerer Interaktionspartner für GPR30, darunter das PALS1-assoziierten Tight Junction-Protein (PATJ) und das FUN14 domain containing 2- Protein (FUNDC2). Durch anschließende Ko-Immunopräzipitation (CoIP)-Experimente konnte die Interaktion von GPR30 mit PATJ validiert werden. Zusätzlich wurde eine teilweise zelluläre Ko-Lokalisation gefunden. Des Weiteren konnte in dieser Arbeit die Wirkung von FSS auf die Expression von GPR30 in HUVEC-Zellen bestätigt und ebenfalls in weiteren anderen Endothelzellen gezeigt werden. So wurde eine Hoch-regulierung der Expression von GPR30 induziert durch FSS in humanen arteriellen Nabelschnul-Endothelzellen (HUAECs), humanen Aorten-Endothelzellen (HAoECs) und in humanen mikrovaskulären Endothelzellen (HMEC-1) gefunden, was darauf hindeutet, dass GPR30 in der Tat eine wichtige Rolle in der vaskulären Physiologie spielt. Abschließend wurde die Rolle von GPR30 und PATJ bei der Reaktion auf FSS auf transkriptioneller Ebene in HMEC-1-Zellen ii genomweit untersucht. Interessanterweise war eine Gruppe von Genen aufgrund von FSS in Zellen, die GPR30 überexprimierten dereguliert, als alleine durch FSS. Darunter waren Gene, die zum einen eine wichtige Rolle bei verschiedenen Funktionen und der Morphogenese von Gefäßen spielen, z.B. Plexin D1 (PLXND1) und Troponin I Typ 3 (TNNI3) und zum anderen an der Entwicklung und der Funktion des endokrinen Systems beteiligt sind, z.B. der ras-related and E2-regulated growth inhibitor (RERG), der in der E2- Signalkaskade involviert ist. Zusammenfassend zeigt diese Arbeit zum ersten Mal die Interaktion von GPR30 und PATJ und beschreibt ein Modell, mit dessen Hilfe die Funktion von GPR30 in Endothelzellen weiter untersuchen könnte. Schlagwörter: GPR30, fluid shear stress, PATJ, endothelzellen. iii ABSTRACT In 1997, the orphan G protein-coupled receptor 30, GPR30 was cloned using human umbilical vein endothelial cells (HUVECs) exposed to fluid shear stress (FSS), one of the mechanical forces acting on blood vessels. Takada et al. have shown that the level of GPR30 expression was markedly induced in response to FSS. Subsequently, in a study performed in the laboratory where the work for this thesis was carried out, the cellular and tissue distribution of GPR30 were investigated in GPR30-LacZ reporter mice and the expression was found predominantly in the endothelial cells of small arteries in several tissue types. GPR30, was claimed some years later to bind 17-β-estradiol (E2) directly and to mediate rapid non-genomic signalling. In contrast, various reports have indicated that E2 fails to bind GPR30 in a specific manner. Despite the controversy on whether GPR30 is an estrogen receptor or still an orphan receptor, nothing is known at present about its relation and interaction with other proteins. Therefore, also according to several reports suggesting that GPCRs interact with and are regulated by several other proteins beyond the established role of heterotrimeric G proteins, the aim of the work described in this thesis was to identify human GPR30 protein interaction partners and to establish a human vascular in vitro model in order to evaluate the potential role of GPR30 and the downstream effects of the interaction between GPR30 and new interaction partners in a vascular model at transcript level. The screening of a human heart cDNA library using the yeast two-hybrid (Y2H) assay led to the identification of several interaction partners for GPR30, among them PALS1-associated tight junction protein (PATJ) and the FUN14 domain containing 2 (FUNDC2). These interactions were verified by co-immunoprecipitation (CoIP) experiments and the interaction of GPR30 with PATJ could be confirmed. The effect of FSS on the expression of GPR30 was confirmed in HUVECs and was detected in other endothelial cell types. In Human Umbilical Arterial (HUAECs), Human Aortic (HAoECs) and Human Microvascular Endothelial Cells (HMEC-1) GPR30 was also found up-regulated upon FSS, suggesting that GPR30 may indeed play a key role in vascular physiology. Finally, the role of GPR30 and PATJ in the FSS response was investigated at the genome-wide transcript level in HMEC-1 cells. Interestingly, a different panel of genes was deregulated owing to FSS in cells over-expressing GPR30 compared to FSS alone. These included genes that play an important role in vascular function and morphogenesis, e.g. plexin D1 (PLXND1) and troponin I type 3 (TNNI3), and in the development and function of the endocrine system, e.g. the ras-related and E2-regulated growth inhibitor (RERG), which is involved in E2 signalling. Taken together, this study provides evidence for the first time for an interaction between GPR30 and PATJ and proposes a model to further evaluate the role of GPR30 in endothelial cells. Keywords: GPR30, fluid shear stress, PATJ, endothelial cells. iv TABLE OF CONTENTS ZUSAMMENFASSUNG.............................................................................................. II ABSTRACT ...............................................................................................................IV TABLE OF CONTENTS .............................................................................................V ABBREVIATIONS ...................................................................................................VIII LIST OF FIGURES ....................................................................................................XI LIST OF TABLES....................................................................................................XIII 1 INTRODUCTION ................................................................................................. 1 1.1 G protein-coupled receptors (GPCRs)............................................................................................. 1 1.1.1 Classification of GPCRs ................................................................................................................... 2 1.1.2 Activation and termination of GPCR signalling ............................................................................... 3 1.1.3 GPCR interacting proteins................................................................................................................ 5 1.2 The G protein-coupled receptor GPR30 .......................................................................................... 6 1.2.1 GPR30: a new estrogen receptor or still an orphan receptor? ...................................................... 7 1.2.2 GPR30 signalling .............................................................................................................................. 9 1.2.3 GPR30 cellular localisation ............................................................................................................10 1.2.4 GPR30 in vivo studies ....................................................................................................................11
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