Epithelial-Mesenchymal-Transition: roles and regulation of myosin II

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DESCRIPTION (provided by applicant): The long-term goal of this project is to understand how cells regulate cellular force production that drives cell migration and other contractile behaviors such as invasion and matrix remodeling. The current submissions focuses on a model of epithelial-to-mesenchymal transition (EMT), in which normal mouse mammary gland cells, which are epithelial in behavior, can be triggered to switch to a mesenchymal, more invasive state in response to the cytokine TGFb. We have recently discovered dramatic regulation of myosin II functions during EMT in this mammary gland model, including nonmuscle myosin II isoform switch, and an upregulation of MHC phosphorylation. Given earlier studies by our group and others documenting MHC phosphorylation as a critical regulator of myosin II filament assembly control during cell migration, our new studies support a model that myosin II isoform switches and MHC phosphorylation may be critical mediators of the enhanced invasive migration behavior and invasiveness that is a hallmark of the switch to the mesenchymal state. We propose a series of cell biological studies to establish the mechanical role of the induced myosin II isoform (myosin IIB), to establish the role of myosin II heavy chain phosphorylation that is induced during EMT, and to identify how cells that go through EMT upregulate myosin II heavy chain phosphorylation. At a broad level, these studies have relevance for understanding how cells upregulate their motility behavior during normal developmental events such as mesoderm initiation and neural tube formation. These studies also have strong relevance to understanding developmental decisions that occur during mammary ductal formation, where cells differentiate towards epithelial versus mesenchymal fates. Finally, these studies have very strong relevance to understanding how cellular contractile/motility machinery is upregulated in pathological settings such as tumor progression to metastatic states and tissue fibrosis.