7. Abstract For the past 23 years, our lab has focused on one of biology's central questions--how does the single cell zygote self-assemble itself into the complex body plan of an animal? Beginning with the dual functions of - catenin in cell adhesion and Wnt signaling, we focused our research in two different areas. In our first project, we explore how cells utilize cell-cell interactions to change shape, move, and assemble polarized tissues during morphogenesis and maintain these during tissue homeostasis, and how cells integrate different tools in the complex actin regulatory toolkit to create diverse actin structures. We explore this in Drosophila, using a highly multidisciplinary approach, and recently expanded to include parallel studies in cultured mammalian cells. Proteins on which we focus play key roles in mammalian development and cancer metastasis. Our current efforts explore two key issues in the field. First, we will determine the mechanisms by which cells link cell-cell junctions to the actomyosin cytoskeleton to allow cell shape change without disrupting epithelial integrity. We hypothesize that cells use different linkers and junctional architectures to drive different key cell shape change or migratory events. Second, we will build on the existing knowledge of the biochemical functions of individual actin regulators to define how cells integrate these to create the diverse actin structures required during normal development, and how upstream signaling pathways shape this integration. In our second project, we explore how cells choose and maintain fate, using Wnt signaling as a model. Wnt signaling shapes virtually every organ system, plays a key role in homeostasis in many tissues, and is inappropriately activated in several common forms of cancer, including colon cancer, the second leading cause of cancer deaths. In the past ten years we focused on the tumor suppressor Adenomatous polyposis coli (APC), a key negative regulator of the Wnt signaling that is mutated in 80% of all colon cancers. APC also plays Wnt- independent roles in regulating the cytoskeleton, thus facilitating high-fidelity chromosome segregation, which is also disrupted in cancer. Our long-term goal is to determine how APC and its protein partners regulate both Wnt signaling and the cytoskeleton during normal development and homeostasis, and how that goes wrong in cancer. In the next funding period we will address two key questions in the field. First, we will define the mechanisms by which the multiprotein destruction complex targets the Wnt effector -catenin for phosphorylation, transfers it to an E3 ligase for ultimate proteasomal destruction, and how Wnt signals regulate its activity. This is a paradigm for how regulated protein stability regulates cell signaling. Second, we will explore the regulation of genome stability, defining how APC acts as a cytoskeletal regulator to ensure mitotic fidelity, and defining mechanisms that buffer its loss. More broadly, we will determine how the genetic circuitry of mitotic regulation and checkpoints is re-drawn in different tissues to meet different needs, contrasting epithelial cells and neural progenitors, using our newly developed Drosophila model of microcephaly.
To form tissues and organs, cells must choose and maintain cell fates via cell-cell communication, adhere to one another, and must act together, by coordinating their cytoskeletons. Disruptions in cell adhesion and cell migration cause certain birth defects, contribute to blistering skin diseases and congenital heart disease, and also play a role in cancer metastasis, while most cases of colon cancer and many lung and endometrial tumors have inappropriate activation of the Wnt cell-cell signaling pathway, due to mutations in genes like the tumor supressor APC. We developed model systems to explore how cell signaling, cell adhesion and the cytoskeleton are normally regulated, to allow better understanding of what goes wrong in human disease.
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