The keratin-desmosome scaffold as a signaling module during epithelial differentiation and wound healing

角蛋白-桥粒支架作为上皮分化和伤口愈合过程中的信号模块

• 批准号: 251212429
• 负责人: Professor Dr. Thomas Magin
• 金额: --
• 依托单位: Professur für Zell- und Entwicklungsbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/251212429?language=en
• 关键词: keratin; desmosome; scaffold; signaling; module

TThe keratin-desmosome scaffold has a dual role in regulating epidermal differentiation through crosstalk with growth factors, in addition to mediating intercellular adhesion and force resistance. Differentiation, wound healing and pathogenesis require remodelling of the keratin desmosome complex at various levels to mediate strong adhesion in the former and weaker adhesion in the latter setting. The functional significance of keratin isotypes for the regulation of desmosomal adhesion, epidermal differentiation and wound healing is not well understood.We have recently established a series of mice and keratinocyte cell lines that lack all or re-express distinct sets of keratins. Their analysis has revealed an active role of keratins in desmosome maintenance impacting on keratinocyte migration and invasion. We demonstrated that keratin-dependent sequestration of a Rack1 PKCa scaffold mediates desmoplakin phosphorylation, cell adhesion and regulates desmosomal protein internalization. Further, we identified a keratin isotype dependent activation of Src as an upstream regulator of desmosomal adhesion. This strongly suggests a role of keratins in inside-out signaling. We hypothesize that the keratin-desmosome scaffold acts as signalling node which receives and modulates growth factor signals in a keratin isotype dependent manner to control cell adhesion, cell signalling and to maintain epithelial cell fate.Our project will elucidate major mechanisms by which keratin isotypes affect epidermal differentiation and wound healing through regulating desmosomal adhesion and turnover. To understand this, we will dissect the crosstalk between IGFR and EGFR signalling and the keratin desmosome scaffold. The long-term aim is to understand the role of the keratin-desmosome complex during carcinogenesis and metastasis and its regulation by oncogenes and EMT activators like snail and ZEB1. To understand the interaction and regulation of the keratin-desmosome complex during keratinocyte differentiation and wound healing, we will pursue the following major objectives:1. Analysis of epidermal differentiation and wound healing as a function of keratin isotypes and their interaction with desmosomes in keratinocytes 2. Wound healing analysis in keratin deficient mice in vivo3. Response of keratin isotype desmosome interactions to signalling downstream of the IGF and EGF receptor4. Dissection of keratin isotype-dependent inside out regulation of Src kinaseWe expect that this project will contribute significantly to the role of keratin isotypes in cell adhesion and its regulation by IGF and EGF. In the long run, our data will provide a mechanistic understanding for the respective contribution of keratin isotypes to epithelial cell behaviour during wound healing and malignant transformation/metastasis. They will provide the opportunity to affect epithelial cell adhesion, migration and invasion by targeting select keratin isotypes in such settings.

角蛋白-桥粒支架除了介导细胞间粘附和抗力外，还通过与生长因子的串扰调节表皮分化。分化、伤口愈合和发病需要角蛋白桥粒复合体在不同水平上的重塑，以介导前者的强粘附和后者的弱粘附。角蛋白同型在调节桥粒黏附、表皮分化和伤口愈合中的功能意义尚不清楚。我们最近建立了一系列小鼠和角质细胞系，缺乏所有或重新表达不同的角蛋白。他们的分析揭示了角蛋白在桥粒维持中的积极作用，影响角化细胞的迁移和侵袭。我们证明角蛋白依赖的Rack1 PKCa支架隔离介导桥粒蛋白磷酸化、细胞粘附和调节桥粒蛋白内化。此外，我们发现角蛋白同型依赖性Src激活是桥粒粘附的上游调节因子。这有力地表明角蛋白在由内而外的信号传导中起作用。我们假设角蛋白-桥粒支架作为信号节点，以角蛋白同型依赖的方式接收和调节生长因子信号，以控制细胞粘附、细胞信号传导和维持上皮细胞的命运。我们的项目将阐明角蛋白同型通过调节桥粒粘连和周转影响表皮分化和伤口愈合的主要机制。为了理解这一点，我们将剖析IGFR和EGFR信号传导与角蛋白桥粒支架之间的串扰。长期目标是了解角蛋白-桥粒复合物在癌变和转移中的作用，以及癌基因和EMT激活因子如snail和ZEB1对其的调控。为了了解角蛋白-桥粒复合物在角化细胞分化和伤口愈合过程中的相互作用和调控，我们将追求以下主要目标：角质形成细胞中角蛋白同型及其与桥粒相互作用的表皮分化和伤口愈合分析角蛋白缺失小鼠体内创面愈合分析角蛋白同型桥粒相互作用对IGF和EGF受体下游信号传导的响应角蛋白同型依赖性Src激酶内外调控的解剖我们期望该项目将对角蛋白同型在细胞粘附及其受IGF和EGF调控中的作用做出重大贡献。从长远来看，我们的数据将为角蛋白同型在伤口愈合和恶性转化/转移过程中对上皮细胞行为的各自贡献提供机制理解。在这种情况下，它们将通过靶向选择角蛋白同型来影响上皮细胞的粘附、迁移和侵袭。

项目成果

Cross talk between the cytoplasm and nucleus during development and disease.

• DOI: 10.1016/j.gde.2016.03.007
• 发表时间: 2016-04
• 期刊: Current opinion in genetics & development
• 影响因子: 4
• 作者: L. Wallrath;J. Bohnekamp;T. Magin

A keratin scaffold regulates epidermal barrier formation, mitochondrial lipid composition, and activity.

• DOI: 10.1083/jcb.201404147
• 发表时间: 2015-12-07
• 期刊: The Journal of cell biology
• 作者: Kumar V;Bouameur JE;Bär J;Rice RH;Hornig-Do HT;Roop DR;Schwarz N;Brodesser S;Thiering S;Leube RE;Wiesner RJ;Vijayaraj P;Brazel CB;Heller S;Binder H;Löffler-Wirth H;Seibel P;Magin TM
• 通讯作者: Magin TM

Keratin defects trigger the itch-inducing cytokine thymic stromal lymphopoietin via Areg-Egfr signaling.

角蛋白缺陷通过 Areg-Egfr 信号传导触发致痒细胞因子胸腺基质淋巴细胞生成素

• DOI: 10.1016/j.jaci.2019.07.041
• 发表时间: 2019
• 期刊: The Journal of allergy and clinical immunology
• 作者: A Scheffschick;D Kiritsi;TM Magin
• 通讯作者: TM Magin