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

项目摘要/摘要 这个项目的长期目标是了解细胞如何调节细胞力的产生。 这推动了细胞迁移和其他收缩行为，如侵袭和基质重塑。 目前的提交集中在上皮向间充质转化(EMT)的模型上，在该模型中 正常的小鼠乳腺细胞在行为上是上皮性的，可以被触发切换到 间质，对细胞因子TGFb的反应更具侵袭性。 我们最近发现在EMT过程中肌球蛋白II功能的戏剧性调节 乳腺模型，包括非肌肉肌球蛋白II亚型开关和MHC的上调 磷酸化。给出了我们小组和其他人关于MHC磷酸化的早期研究 作为细胞迁移过程中肌球蛋白II微丝组装的关键调节因子，我们的新研究 支持肌球蛋白II亚型开关和MHC磷酸化可能是关键介质的模型 增强的侵入性迁移行为和侵袭性，这是向 间充质状态。我们提出了一系列的细胞生物学研究，以建立机械作用 诱导肌球蛋白II亚型(Myosin IIB)，以确定肌球蛋白II重链的作用 在EMT过程中诱导的磷酸化，并确定经历EMT的细胞如何上调 肌球蛋白II重链磷酸化。 在广泛的水平上，这些研究对于理解细胞如何上调其基因表达具有相关性 中胚层启动和神经管等正常发育事件中的运动行为 队形。这些研究也与理解发展决策有很强的相关性 发生在乳腺导管形成期间，在那里细胞向上皮细胞分化，而不是 间充质的命运。最后，这些研究对于理解细胞如何 收缩/运动机制在病理环境中上调，如肿瘤进展到 转移状态和组织纤维化。

PROJECT SUMMARY/ABSTRACT 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.