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

上皮-间充质-转化：肌球蛋白 II 的作用和调节

• 批准号: 9262931
• 负责人: THOMAS EGELHOFF
• 金额: $ 37.83万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262931
• 关键词: Actomyosin; Address; Adhesions; Apical; Atomic Force Microscopy; Attention; Behavior; Biochemical; Biological; Biological Assay; C-terminal; Cell Differentiation process; Cells; Collagen; Cytoskeleton; Defect; Development; Disease; Embryonic Development; Epithelial; Event; Fibroblast Growth Factor; Fibrosis; Filament; Focal Adhesions; Gel; Gene Chips; Generations; Goals; Heart Valves; Image; Impairment; Intercellular Junctions; MADH2 gene; Mammary Duct; Mammary gland; Mechanics; Mediating; Mediator of activation protein; Mesenchymal; Mesoderm; Messenger RNA; Metastatic to; Microfluidics; Modeling; Mus; Mutation; Myosin ATPase; Myosin Heavy Chains; Myosin Type II; Neoplasm Metastasis; Nervous system structure; Neural tube; Nonmuscle Myosin Type IIA; Nonmuscle Myosin Type IIB; Nuclear Translocation; Organ; Pathologic; Phosphorylation; Phosphorylation Site; Phosphotransferases; Photobleaching; Process; Production; Protein Isoforms; Proteins; Pulmonary Fibrosis; Recovery; Recruitment Activity; Regulation; Role; Series; Signal Pathway; Site; Surface; Testing; Tissues; Traction; Transitional Cell; Up-Regulation; cell motility; cell type; cellular imaging; cytokine; epithelial to mesenchymal transition; inhibitor/antagonist; migration; mouse model; mutant; non-muscle myosin; novel; protein function; public health relevance; response; small hairpin RNA; transcription factor; tumor progression

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.

描述（由申请人提供）：该项目的长期目标是了解细胞如何调节驱动细胞迁移和其他收缩行为（例如入侵和基质重塑）的细胞力产生。目前的提交着重于上皮到间质转变（EMT）的模型，其中可以触发正常的小鼠乳腺细胞（在行为上都是上皮的细胞），以切换到间充质，更具侵入性状态，以响应细胞因子TGFB。 在此乳腺模型中，我们最近发现了EMT期间肌球蛋白II功能的戏剧性调节，包括非肌肉肌球蛋白II同工型开关以及MHC磷酸化的上调。给出了我们的小组和其他记录MHC磷酸化作为细胞迁移期间肌球蛋白II细丝组装控制的关键调节的研究，我们的新研究支持了一个模型，即肌球蛋白II同工型转换和MHC磷酸化可能是增强侵入性迁移行为和象征性状态的关键介体，这是对切换的Hall swissemal sectalmal sechand sechnemal sechnemal sench eNceph sephsempal nonge。我们提出了一系列细胞生物学研究，以确定诱导的肌球蛋白II同工型（肌球蛋白IIB）的机械作用，以确定EMT期间诱导的肌球蛋白II重链磷酸化的作用，并确定通过EMT通过EMT的细胞上调肌球蛋白II II重链磷酸化。 在广泛的水平上，这些研究与了解细胞在正常发育事件（例如中胚层开始和神经管形成）中如何上调其运动行为有关。这些研究还与理解乳腺导管形成过程中发生的发育决策具有很强的相关性，在乳腺导管形成过程中，细胞与上皮和间质命运区分开。最后，这些研究与了解细胞收缩/运动机制如何在病理环境（例如肿瘤发展为转移性状态和组织纤维化）中上调。

项目成果

Increased cancer stem cell invasion is mediated by myosin IIB and nuclear translocation.

• DOI: 10.18632/oncotarget.9896
• 发表时间: 2016-07-26
• 期刊: Oncotarget
• 作者: Thomas D;Thiagarajan PS;Rai V;Reizes O;Lathia J;Egelhoff T
• 通讯作者: Egelhoff T

Release of nonmuscle myosin II from the cytosolic domain of tumor necrosis factor receptor 2 is required for target gene expression.

• DOI: 10.1126/scisignal.2003743
• 发表时间: 2013-07-16
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Chandrasekharan UM;Dechert L;Davidson UI;Waitkus M;Mavrakis L;Lyons K;Beach JR;Li X;Egelhoff TT;Fox PL;DiCorleto PE
• 通讯作者: DiCorleto PE

Keratin 5-Cre-driven excision of nonmuscle myosin IIA in early embryo trophectoderm leads to placenta defects and embryonic lethality.

• DOI: 10.1016/j.ydbio.2013.07.017
• 发表时间: 2013-10-01
• 期刊: DEVELOPMENTAL BIOLOGY
• 影响因子: 2.7
• 作者: Crish, James;Conti, Mary Anne;Sakai, Takao;Adelstein, Robert S.;Egelhoff, Thomas T.
• 通讯作者: Egelhoff, Thomas T.

Mammalian target of rapamycin complex 2 (mTORC2) is a critical determinant of bladder cancer invasion.

• DOI: 10.1371/journal.pone.0081081
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Gupta S;Hau AM;Beach JR;Harwalker J;Mantuano E;Gonias SL;Egelhoff TT;Hansel DE
• 通讯作者: Hansel DE

TNFR2 Depletion Reduces Psoriatic Inflammation in Mice by Downregulating Specific Dendritic Cell Populations in Lymph Nodes and Inhibiting IL-23/IL-17 Pathways.

• DOI: 10.1016/j.jid.2021.12.036
• 发表时间: 2022-08
• 期刊: JOURNAL OF INVESTIGATIVE DERMATOLOGY
• 影响因子: 6.5
• 作者: Chandrasekharan, Unnikrishnan M.;Kaur, Raminderjit;Harvey, Jennifer E.;Braley, Chad;Rai, Vandana;Lee, MacKenzie;de Windt, Nicholas;Hsieh, Jason;Jaini, Ritika;Bayik, Defne;Scheraga, Rachel G.;Fernandez, Anthony P.;DiCorleto, Paul E.;Husni, M. Elaine
• 通讯作者: Husni, M. Elaine