Regulation of Cadherins by MLK3
MLK3 对钙粘蛋白的调节
基本信息
- 批准号:10793060
- 负责人:
- 金额:$ 45.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-22 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:Adherens JunctionAdhesionsBiological ProcessBreastCadherinsCarcinomaCell AdhesionCell-Cell AdhesionCellsCo-ImmunoprecipitationsComplexDevelopmentE-CadherinEpithelial CellsEpitheliumExperimental DesignsGene ExpressionGrowth Factor ReceptorsHumanIntercellular JunctionsInvadedMAP Kinase Kinase KinaseMalignant NeoplasmsMammalian CellMatrix MetalloproteinasesMediatingMesenchymalMitogen-Activated Protein KinasesMorphogenesisMultiprotein ComplexesN-CadherinNeurofibromin 2OvarianPhosphorylationPhosphotransferasesProcessProliferatingProtein KinaseProteinsReceptor SignalingRegulationResearchRoleSignal PathwaySmall Interfering RNAStructureTestingTissuesTranscription Repressorbeta catenincancer cellcell motilityinsightknock-downmigrationmixed lineage kinase 3neoplastic cellnovelovarian neoplasmoverexpressionprotein complexslug
项目摘要
ABSTRACT
Mixed lineage kinase (MLK) 3 is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that
regulates multiple MAPK signaling pathways in mammalian cells. In addition, MLK3 has been demonstrated to
regulate proliferation and invasion of different types of human epithelial cells (normal and cancer) including
ovarian and breast. In the current study, we identified a novel function for MLK3 in cell-cell adhesion of ovarian
epithelial TOV112D tumor cells. MLK3 siRNA knockdown disrupted cell-cell adhesion in TOV112D spheroids,
reduced the cell junction protein, E-cadherin, and dramatically increased the level of Slug, a transcriptional
repressor of E-cadherin. Furthermore, MLK3 was co-immunoprecipitated with E-cadherin in TOV112D cell
lysates, which indicates that MLK3 may be associated with adherens junction protein complexes. Additionally,
MLK3 overexpression induced the cleavage of E-cadherin resulting in an 80 kDa soluble form of E-cadherin,
which has been found to activate growth factor receptor signaling. In TOV112D cells, MLK3 overexpression
also strongly induced the expression of N-cadherin, a cell junction protein that is normally expressed in
mesenchymal cells. Our central hypothesis is that MLK3 regulates E-cadherin and N-cadherin through multiple
mechanisms, and this regulation is essential for proper cell adhesion and migration in ovarian epithelial cells.
The proposed experiments are designed to define the mechanism(s) by which MLK3 regulates E- and N-
cadherin, and the impact of this regulation on ovarian cell spheroid adhesion and migration. Three specific
aims are proposed to test the hypothesis. In Aim 1, we will investigate MLK3 functions in E-cadherin multi-
protein complexes and ovarian spheroid cell-cell adhesion. In aim 2, we will examine MLK3-dependent
regulation of Slug and E-cadherin expression. In Aim 3, we will evaluate MLK3-dependent regulation of E-
Cadherin cleavage, N-Cadherin expression and ovarian spheroid structure. This research will reveal novel
insight into the mechanisms by which MLK3 functions to regulate E- and N-cadherin and modulate cell-cell
adhesion and migration, processes which are essential for development, tissue morphogenesis, migration and
cancer cell invasion.
摘要
混合谱系激酶(MLK)3是一种有丝分裂原激活的蛋白激酶(MAPK),
在哺乳动物细胞中调节多种MAPK信号通路。此外,MLK3已经被证明
调节不同类型的人上皮细胞(正常和癌症)的增殖和侵袭,包括
卵巢和乳房。在本研究中,我们发现了MLK3在卵巢细胞间黏附中的新功能。
上皮性TOV112D肿瘤细胞。MLK3 siRNA敲除TOV112D球体中的细胞-细胞黏附,
减少细胞连接蛋白,E-钙粘素,并显著提高Slug的水平,转录
E-钙粘附素的抑制因子。此外,MLK3与E-钙粘蛋白在TOV112D细胞中免疫共沉淀
裂解产物,表明MLK3可能与黏附连接蛋白复合体有关。另外,
MLK3过表达诱导E-钙粘蛋白的裂解,导致80 kDa的可溶性E-钙粘蛋白,
已经发现它可以激活生长因子受体信号。在TOV112D细胞中,MLK3过表达
也强烈诱导N-钙粘蛋白的表达,这是一种细胞连接蛋白,通常在
间充质细胞。我们的中心假设是MLK3通过多种途径调节E-钙粘蛋白和N-钙粘蛋白
这种调节对于卵巢上皮细胞的正常黏附和迁移是必不可少的。
拟议的实验旨在确定MLK3调节E-和N-的机制(S)。
钙粘附素,以及这一调节对卵巢细胞球体黏附和迁移的影响。三个具体的
为了检验这一假说,本文提出了目标。在目标1中,我们将研究MLK3在E-钙粘附素多途径中的作用。
蛋白质复合体与卵巢球状细胞-细胞黏附。在目标2中,我们将研究MLK3依赖
鼻涕蛋白和E-钙粘附素的表达调控。在目标3中,我们将评估MLK3依赖的E-
钙粘附素切割、N-钙粘附素表达与卵巢球体结构。这项研究将揭示小说
MLK3调节E-和N-钙粘蛋白及调节细胞-细胞机制的研究
黏附和迁移,对发育、组织形态形成、迁移和
癌细胞的侵袭。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Deborah N Chadee其他文献
Deborah N Chadee的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Deborah N Chadee', 18)}}的其他基金
Regulation of MLK3 by oxidative stress in colon cancer cells
结肠癌细胞中氧化应激对 MLK3 的调节
- 批准号:
9097305 - 财政年份:2016
- 资助金额:
$ 45.15万 - 项目类别:
Regulation of Mixed Lineage Kinase 3 by the tumor suppressor protein Merlin
肿瘤抑制蛋白 Merlin 对混合谱系激酶 3 的调节
- 批准号:
7364459 - 财政年份:2008
- 资助金额:
$ 45.15万 - 项目类别:
相似海外基金
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y004841/1 - 财政年份:2024
- 资助金额:
$ 45.15万 - 项目类别:
Research Grant
Defining a role for non-canonical mTORC1 activity at focal adhesions
定义非典型 mTORC1 活性在粘着斑中的作用
- 批准号:
BB/Y001427/1 - 财政年份:2024
- 资助金额:
$ 45.15万 - 项目类别:
Research Grant
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y005414/1 - 财政年份:2024
- 资助金额:
$ 45.15万 - 项目类别:
Research Grant
Development of a single-use, ready-to-use, sterile, dual chamber, dual syringe sprayable hydrogel to prevent postsurgical cardiac adhesions.
开发一次性、即用型、无菌、双室、双注射器可喷雾水凝胶,以防止术后心脏粘连。
- 批准号:
10669829 - 财政年份:2023
- 资助金额:
$ 45.15万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10587090 - 财政年份:2023
- 资助金额:
$ 45.15万 - 项目类别:
Improving Maternal Outcomes of Cesarean Delivery with the Prevention of Postoperative Adhesions
通过预防术后粘连改善剖宫产的产妇结局
- 批准号:
10821599 - 财政年份:2023
- 资助金额:
$ 45.15万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10841832 - 财政年份:2023
- 资助金额:
$ 45.15万 - 项目类别:
Prevention of Intraabdominal Adhesions via Release of Novel Anti-Inflammatory from Surface Eroding Polymer Solid Barrier
通过从表面侵蚀聚合物固体屏障中释放新型抗炎剂来预防腹内粘连
- 批准号:
10532480 - 财政年份:2022
- 资助金额:
$ 45.15万 - 项目类别:
I-Corps: A Sprayable Tissue-Binding Hydrogel to Prevent Postsurgical Cardiac Adhesions
I-Corps:一种可喷雾的组织结合水凝胶,可防止术后心脏粘连
- 批准号:
10741261 - 财政年份:2022
- 资助金额:
$ 45.15万 - 项目类别:
Sprayable Polymer Blends for Prevention of Site Specific Surgical Adhesions
用于预防特定部位手术粘连的可喷涂聚合物共混物
- 批准号:
10674894 - 财政年份:2022
- 资助金额:
$ 45.15万 - 项目类别: