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The role of the actin cytoskeleton in the regulation of the Hippo pathway

Boek - Dissertatie

The Hippo pathway effectors YAP (Yes-associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) promote organ growth and tumorigenesis and are indicated as promising targets for cancer therapy. This is because they are hyperactivated with high frequency in different types of human cancer, because their knockout or knockdown suppressed tumor development and maintenance in various preclinical cancer models, and because their deletion in adult mice has minimal acute effects in tissues tested. Given the significance of YAP/TAZ activation in tumor development and maintenance, developing YAP/TAZ inhibitors has been attempted worldwide and multiple drugs that inhibit YAP/TAZ-TEAD protein-protein interaction were reported. Although most of these inhibitors are able to block YAP/TAZ activity, additional target molecules are needed to overcome possible problems about the potency, selectivity, and toxicity of YAP/TAZ inhibitors. Therefore, understanding how YAP/TAZ become hyperactive, and finding the upstream activating factors that are responsible for YAP/TAZ hyperactivation specifically in cancer is essential. Many studies aimed to discover factors and processes that cause YAP/TAZ activation in normal homeostasis and cancer. This led to the identification of cell polarity molecules, components of different types of cell junctions as well as classical signaling pathways such as Ras-MAPK, Wnt/b-catenin and GPCRs as regulators of YAP/TAZ activity. Among the identified regulators, the most prominent is the changes in actin cytoskeleton structure. Actin accumulation was discovered as a conserved positive inducer of YAP/TAZ activity in different species both in vitro and in vivo. However, whether there is a specific actin polymerization mechanism that causes YAP/TAZ activity, and the biological consequences of this regulation have never been extensively studied. In this study, by using fly wing imaginal discs and mouse liver, we analyzed the role actin polymerization-dependent YAP/TAZ activation in tumor development.
Jaar van publicatie:2022
Toegankelijkheid:Closed