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

项目总结/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 驱动细胞迁移和其他收缩行为，如侵入和基质重塑。 目前提交的材料集中于上皮-间充质转化（EMT）的模型，其中 正常的小鼠乳腺细胞，在行为上是上皮细胞，可以被触发切换到 间充质，更侵入性的状态，响应于细胞因子TGF β。 我们最近发现，在EMT过程中，肌球蛋白II的功能受到了戏剧性的调节， 乳腺模型，包括非肌肉肌球蛋白II亚型转换和MHC上调 磷酸化鉴于我们小组和其他人早期的研究记录了MHC磷酸化 作为细胞迁移过程中肌球蛋白II细丝组装控制的关键调节剂，我们的新研究 支持肌球蛋白II亚型转换和MHC磷酸化可能是关键介质模型 增强的侵入性迁移行为和侵入性，这是向 间充质状态我们提出了一系列的细胞生物学研究，以建立机械的作用， 诱导肌球蛋白II亚型（肌球蛋白IIB），建立肌球蛋白II重链的作用 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。 在广泛的层面上，这些研究与理解细胞如何上调其细胞周期有关。 在正常发育过程中的运动行为，如中胚层起始和神经管 阵这些研究也与理解发展决定有很大的相关性， 发生在乳腺导管形成期间，其中细胞向上皮细胞分化， 间充质命运最后，这些研究与理解细胞如何 收缩/运动机制在病理环境中被上调，例如肿瘤进展到 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.