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Forces and signal transduction by desmosomal cadherins

桥粒钙粘蛋白的力和信号转导

基本信息

批准号：
290004423
负责人：
Professor Dr. Volker Spindler
金额：
--
依托单位：
Anatomisches Institut
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/290004423?language=en
关键词：
Forces signal transduction desmosomal cadherins

项目摘要

Desmosomal cadherins (DCs) are transmembrane adhesion molecules located inside desmosomes and also found extradesmosomal in the membrane. Within desmosomes, DCs are coupled intracellularly to the plaque proteins plakophilin and plakoglobin. Desmoplakin connects the plaque to the intermediate filament cytoskeleton. This construct provides intercellular adhesive strength to tissues subjected to high degrees of mechanical stress such as the epidermis or the heart muscle which can be concluded from severe diseases arising from impaired DC function. However, the adhesive properties of DCs have not been characterized so far and the functions of extradesmosomal DCs in the membrane are largely unknown. Recent evidence demonstrates that DCs, in addition to their adhesive function, shape cell behavior via modulating intracellular signaling in an adhesion-dependent manner. Here, the extradesmosomal DCs may play a crucial role. To gain further insights into these functions, the proposal aims to characterize the adhesive and the signaling properties of DCs via biophysical and biochemical approaches in living keratinocytes. We will evaluate (i) the distribution, binding partners and binding characteristics of specific DC isoforms in living keratinocytes using atomic force microscopy (AFM) and optical trapping approaches and (ii) determine whether these parameters are dependent on the anchorage to the cytoplasmic plaque. Here we will apply murine keratinocytes deficient for plakoglobin, desmoplakin and keratin filaments. To investigate outside-in-signaling elicited by DCs in an adhesion-dependent manner, we will (iii) use FRET probes and biochemical assays to measure the activity of p38MAPK, RhoA, PKC and Src after interference with the binding of specific DC isoforms with antibodies or peptides. Because these molecules are also known to modulate keratinocyte cohesion, we finally will (iv) evaluate how the distribution and binding properties of DCs are altered by inside-out signaling via these signaling pathways. Taken together, these experiments will provide novel insights into the function of specific DCs and their roles as receptors and targets of intracellular signaling.

桥粒钙粘附素(DCs)是一种跨膜黏附分子，位于桥粒内，也存在于膜外。在桥粒内，树突状细胞与亲斑蛋白和球蛋白偶联。桥粒蛋白将斑块与中间细丝细胞骨架连接起来。这种结构为承受高度机械应力的组织(如表皮或心肌)提供了细胞间黏附强度，这些组织可以从DC功能受损引起的严重疾病中得出结论。然而，到目前为止，树突状细胞的黏附特性尚不清楚，桥粒外树突状细胞在膜上的功能也很不清楚。最近的证据表明，DC除了具有黏附功能外，还通过以黏附依赖的方式调节细胞内信号转导来塑造细胞行为。在这方面，桥粒外树突状细胞可能起着至关重要的作用。为了进一步了解这些功能，该提案旨在通过生物物理和生化方法在活体角质形成细胞中表征DC的粘附性和信号特性。我们将使用原子力显微镜(AFM)和光学捕捉方法评估(I)特定DC亚型在活体角质形成细胞中的分布、结合伙伴和结合特性，以及(Ii)确定这些参数是否依赖于细胞质斑块的锚定。在这里，我们将使用缺乏白蛋白、桥粒蛋白和角蛋白细丝的小鼠角质形成细胞。为了研究DC以黏附依赖的方式诱导的内外信号，我们将(Iii)使用FRET探针和生化分析来检测干扰特定DC亚型与抗体或多肽结合后p38MAPK、RhoA、PKC和Src的活性。由于这些分子也是已知的调节角质形成细胞凝聚力的分子，我们最终将(Iv)评估DC的分布和结合特性是如何通过这些信号通路由内而外的信号途径改变的。综上所述，这些实验将为了解特定DC的功能以及它们作为细胞内信号传递的受体和靶点的作用提供新的见解。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inhibition of p38MAPK signalling prevents epidermal blistering and alterations of desmosome structure induced by pemphigus autoantibodies in human epidermis

DOI：
10.1111/bjd.15721
发表时间：
2017-12-01
期刊：
BRITISH JOURNAL OF DERMATOLOGY
影响因子：
10.3
作者：
Egu, D. T.;Walter, E.;Waschke, J.
通讯作者：
Waschke, J.

Plakophilin 1 but not plakophilin 3 regulates desmoglein clustering

DOI：
10.1007/s00018-019-03083-8
发表时间：
2019-09-01
期刊：
CELLULAR AND MOLECULAR LIFE SCIENCES
影响因子：
8
作者：
Fuchs, Michael;Foresti, Marco;Vielmuth, Franziska
通讯作者：
Vielmuth, Franziska

Clustering of desmosomal cadherins by desmoplakin is essential for cell-cell adhesion

桥粒斑蛋白对桥粒钙粘蛋白的聚集对于细胞与细胞的粘附至关重要

DOI：
10.1111/apha.13609
发表时间：
2021
期刊：
bioRxiv
影响因子：
0
作者：
Wanuske MT;Brantschen D;Schinner C;Stüdle C;Walter E;Hiermaier M;Vielmuth F;Waschke J;Spindler V
通讯作者：
Spindler V

Loss of desmoglein 2 promotes tumorigenic behavior in pancreatic cancer cells