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The ErbB signaling network comprises a complex dynamic system, which regulates a diverse set of cellular behaviors. In this thesis, we examined how regulating the distribution of ErbB receptors between the plasma membrane and different endosomal compartments enables contextual regulation of receptor activity and signaling. In the first part of this work, we investigated how spatial regulation of EGFR controls its autocatalytic activity. We found that autonomously activated and EGF activated r...
In chemical biology and drug discovery, the development of novel methods for efficient synthesis of structurally distinct molecular scaffolds holds an immense importance. Gold catalyzed enyne cycloisomerizations are a powerful tool to access a wide range of complex molecules owing to the tunable nature of gold complexes with ligand and reaction conditions. A number of reactions have disclosed the role of substrates, ligands of gold(I) catalyst and the nucleophiles to afford a variety of produ...
Nicht-kleinzelliger Lungenkrebs (NSCLC) ist die häufigste Ursache für Krebs-bezogene Todesfälle weltweit.[1] Die Behandlung von NSCLC hat jedoch in den letzten zehn Jahren eine Revolution erfahren: Die Identifizierung von prädiktiven Biomarkern und ein detailliertes Verständnis von deren biochemischen und molekularen Eigenschaften erlaubte die Entwicklung von zielgerichteten, spezifischen Inhibitoren der mutierten Onkoproteine. Diese sogenannte Präzisionsmedizin stellt einen alternativen Beha...
The epidermal growth factor receptor (EGFR), a member of the ErbB family, is a receptor tyrosine kinase that represents a key mediator in critical cellular signaling processes such as cell proliferation, cell cycle regulation as well as apoptosis. Therefore, dysregulation of EGFR plays a pivotal role in the onset and progression of cancer. Mutations in the gene encoding the EGF receptor have been discovered as oncogenic drivers in non-small cell lung cancer (NSCLC). These somatic kinase domai...
Die Verwendung von kleinen organischen Molekülen gegen Rezeptor-Tyrosinkinasen (RTKs) hat sich in der modernen Krebstherapie als wertvolle Therapie-Strategie erwiesen. Die Assoziation von Krebs mit der Dysregulation von Signalwegen, die mit RTKs verbunden sind, ist ein Schlüsselelement in der gezielten Krebstherapie. Die Tyrosinkinase Stammzellenfaktorrezeptor KIT ist ein Beispiel für eine klinisch relevante RTK. KIT ist ein Zielprotein in der Therapie von gastrointestinalen Stroma-tumoren (G...
In dieser Arbeit wurden zwei Strategien zum Aufbau von kompartimentierten GOX/HRP-Reaktionskaskaden untersucht. Die erste Strategie bestand in der Assemblierung der Enzyme im Nanometermaßstab durch Methoden der DNA Nanotechnologie. Hierdurch sollten künstliche Multienzymkomplexe aufgebaut werden, die auf eine mögliche Beschleunigung der Gesamtreaktion durch räumliche Nähe, dem sogenannten „Channeling“, untersucht wurden. Bei der zweiten Strategie wurden die Enzyme in einen Festbettr...
As a major developmental pathway, Hedgehog (Hh) signaling is required for segment polarity in Drosophila and limb pattering in vertebrates. Since its discovery 40 years ago, several studies have identified various pathway components and helped to elucidate the underlying mechanisms of signal transduction. Nevertheless, some regulatory steps during pathway induction are not yet fully understood. Similar to other developmental pathways like Wnt, TGFβ or Notch signaling, also Hh signaling plays ...
Despite having the same "purpose", the uncontrollable cellular growth to the detriment of the organism, cancer presents itself in humans in great variety of forms. This variety makes developing effective treatments a highly challenging task. Nevertheless, cancer has a handful of hallmarks that are present almost ubiquitously in all types of tumours. Among them is the upregulated glucose uptake, known as the Warburg effect. However, there has yet to be a drug or treatment that makes use of thi...
In mammals, DNA methylation is an epigenetic modification and the most widely characterized epigenetic nucleobase is 5-methylcytosine (5mC), that causes downregulation of gene transcription. Several studies have shown a direct link between the presence of 5mC in promoters of tumour suppressor genes and various cancers, autoimmune diseases, metabolic disorders and neurodegenerative ailments such as Schizophrenia, Fragile X and Prader-Willi syndrome. This thesis was focussed on the developmen...
The main function of protein kinases is widely considered the activation of their substrates by catalytic phosphotransfer from adenosine-5‘-triphosphate (ATP), explaining the central role of kinases in cellular signaling cascades. Recently, more and more functions independent from this catalytic mechanism were described, that are involved in several biological processes, e.g., by regulation or localization of their substrates via protein-protein interactions or the formation of multi-enzyme c...
The specific detection of epigenetic marks is required for diagnosis and subsequent treatment of numerous diseases which are based on a disorder of the DNA methylation pattern. In bacteria, the epigenetic signal N6-methyl adenine functions in many cellular processes like genome defense, DNA replication and repair as well as transcription of virulence factors. In the past decade, lots of effort went into the development of protein-DNA recognition systems. The present work is located at the int...
Polymorphonuclear neutrophils are short-lived leukocytes that migrate to infected sites under the acute immune response where they phagocytose, and degranulate to kill microbes. Additionally, neutrophils were found to form Neutrophil Extracellular Traps (NETs). In this process, known as NETosis, the nuclear lobules disappear, the chromatin expands and the DNA is expelled and is decorated with antimicrobial proteins. The signalling mechanisms leading to the formation of NETs are poorly underst...
The discovery of small organic molecules capable of binding to specific biological targets represents a decisive step towards the development of novel therapies for the treatment of human diseases. However, identifying such small bioactive molecules is often a complex process involving numerous challenges, including low-affinity binding to target proteins. This necessitates the development of effective and powerful strategies to generate large sets of chemical compound libraries and novel scr...
Non-alcoholic fatty liver disease (NAFLD) encompasses a wide range of liver diseases, where excessive hepatic lipid accumulation is a common factor. It is highly prevalent worldwide, and is associated with an elevated risk of developing more severe liver diseases, as well as cardiovascular and renal diseases, such as the formation of kidney stones. The aim of this study was to identify and investigate lipid-associated metabolic and functional alterations in steatotic livers and hepatocytes. F...
Phosphorylation of polybasic stretches in membrane-associated proteins creates an electrostatic switch influencing their interactions with membrane lipids. Such modification affects their localization, conformational fluctuations and ultimately function. One example for this is the epidermal growth factor receptor (EGFR), which is involved in the pathogenesis of many cancers. EGFR activation is coupled to a conformational change, where the intracellular domain is released from an autoinhibi...
Naturstoffe bestehen zumeist aus cyclischen und polycyclischen Ringsystemen und sind eine wichtige Quelle bei der Suche nach geeigneten Wirkstoffen. Die Entwicklung geeigneter Cyclisierungsmethoden ist von entscheidener Bedeutung, um Zugang zum Grundgerüst zu erhalten. Gold-katalysierte Umlagerungen von 1,n-Eninen (n = 5−7) erwiesen sich als wirksame Methode zum Aufbau solcher komplexer Strukturen und fanden bereits Anwendung in der Naturstoffsynthese. Gold-katalysierte Cycloisomerisierungen...