更新于：2024-11-01

WLS

更新于：2024-11-01

基本信息

别名

C1orf139、EVI、FLJ23091

+ [9]

简介

Regulates Wnt proteins sorting and secretion in a feedback regulatory mechanism. This reciprocal interaction plays a key role in the regulation of expression, subcellular location, binding and organelle-specific association of Wnt proteins (PubMed:34587386). Plays also an important role in establishment of the anterior-posterior body axis formation during development (By similarity).

关联

项与 WLS 相关的药物

YW-1128

靶点

CTNNB1 x WLS

作用机制

CTNNB1抑制剂 [+1]

在研机构

广州医科大学 [+1]

原研机构

University of Maryland

在研适应症

先天性碳水化合物代谢紊乱 [+3]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

NOV-1502

靶点

CTNNB1 x RAS x WLS

作用机制

CTNNB1 modulators [+2]

在研机构

Yonsei University

原研机构

Yonsei University

在研适应症

实体瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

P-975

靶点

WLS

作用机制

WLS基因调节剂

在研机构

German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

原研机构

German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

在研适应症

脑癌

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 WLS 相关的临床结果

登录后查看更多信息

100 项与 WLS 相关的转化医学

登录后查看更多信息

0 项与 WLS 相关的专利（医药）

登录后查看更多信息

290

项与 WLS 相关的文献（医药）

2024-10-01·PROTEOMICS

The temporal protein signature analyses of developing human deciduous molar tooth germ

Article

作者: Wu, Buling ; Xiong, Fu ; Hu, Liang ; Zhang, Jian ; Chen, Xiaohang ; Wei, Fengxiang ; Zhao, Guoqiang ; Li, Gaochi

AbstractThe tooth serves as an exemplary model for developmental studies, encompassing epithelial‐mesenchymal transition and cell differentiation. The essential factors and pathways identified in tooth development will help understand the natural development process and the malformations of mineralized tissues such as skeleton. The time‐dependent proteomic changes were investigated through the proteomics of healthy human molars during embryonic stages, ranging from the cap‐to‐early bell stage. A comprehensive analysis revealed 713 differentially expressed proteins (DEPs) exhibiting five distinct temporal expression patterns. Through the application of weighted gene co‐expression network analysis (WGCNA), 24 potential driver proteins of tooth development were screened, including CHID1, RAP1GDS1, HAPLN3, AKAP12, WLS, GSS, DDAH1, CLSTN1, AFM, RBP1, AGO1, SET, HMGB2, HMGB1, ANP32A, SPON1, FREM1, C8B, PRPS2, FCHO2, PPP1R12A, GPALPP1, U2AF2, and RCC2. Then, the proteomics and transcriptomics expression patterns of these proteins were further compared, complemented by single‐cell RNA‐sequencing (scRNA‐seq). In summary, this study not only offers a wealth of information regarding the molecular intricacies of human embryonic epithelial and mesenchymal cell differentiation but also serves as an invaluable resource for future mechanistic inquiries into tooth development.

2024-09-01·Traffic

Dissociation of Drosophila Evi‐Wg Complex Occurs Post Apical Internalization in the Maturing Acidic Endosomes

Article

作者: Sharma, Satyam ; Chaudhary, Varun

ABSTRACTSignaling pathways activated by secreted Wnt ligands play an essential role in tissue development and the progression of diseases, like cancer. Secretion of the lipid‐modified Wnt proteins is tightly regulated by a repertoire of intracellular factors. For instance, a membrane protein, Evi, interacts with the Wnt ligand in the ER, and it is essential for its further trafficking and release in the extracellular space. After dissociating from the Wnt, the Wnt‐unbound Evi is recycled back to the ER via Golgi. However, where in this trafficking path Wnt proteins dissociate from Evi remains unclear. Here, we have used the Drosophila wing epithelium to trace the route of the Evi‐Wg (Wnt homolog) complex leading up to their separation. In these polarized cells, Wg is first trafficked to the apical surface; however, the secretion of Wg is believed to occurs post‐internalization via recycling. Our results show that the Evi‐Wg complex is internalized from the apical surface and transported to the retromer‐positive endosomes. Furthermore, using antibodies that specifically label the Wnt‐unbound Evi, we show that Evi and Wg separation occurs post‐internalization in the acidic endosomes. These results refine our understanding of the polarized trafficking of Wg and highlight the importance of Wg endocytosis in its secondary secretion.

2024-09-01·Autophagy

The Wolfram-like variant WFS1 ^E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice

Article

作者: Bataillard, Méghane S. ; Tranebjærg, Lisbeth ; Richard, Elodie M. ; Delprat, Benjamin ; Patergnani, Simone ; Maurice, Tangui ; Cazevieille, Chantal ; Valéro, René ; Pinton, Paolo ; Alves, Stacy ; Danese, Alberto

Dominant variants in WFS1 (wolframin ER transmembrane glycoprotein), the gene coding for a mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein, have been associated with Wolfram-like syndrome (WLS). In vitro and in vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca²⁺) transfer, mitochondrial dysfunction, and enhanced macroautophagy/autophagy and mitophagy. However, in the WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that in human fibroblasts and murine neuronal cultures the WLS protein WFS1^E864K leads to decreases in mitochondria bioenergetics and Ca²⁺ uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in the Wfs1^E864K mouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM's integrity and functionality. It may open new treatment perspectives for patients with WLS.Abbreviations: BafA1: bafilomycin A₁; ER: endoplasmic reticulum; HSPA9/GRP75: heat shock protein family A (Hsp70) member 9; ITPR/IP₃R: inositol 1,4,5-trisphosphate receptor; MAM: mitochondria-associated endoplasmic reticulum membrane; MCU: mitochondrial calcium uniporter; MFN2: mitofusin 2; OCR: oxygen consumption rate; ROS: reactive oxygen species; ROT/AA: rotenone+antimycin A; VDAC1: voltage dependent anion channel 1; WLS: Wolfram-like syndrome; WS: Wolfram syndrome; WT: wild-type.

项与 WLS 相关的新闻（医药）

2023-10-20

·生物谷

Cell：李晓淳团队揭示Wnt生物发生和分泌以及Wnt7特异性信号的分子基础

该研究以Wnt7a的合成、分泌和激活入手，阐释了脂修饰的Wnt蛋白是如何在ER中完成由PORCN向WLS的转移，WLS如何在细胞表面释放Wnt，以及中枢神经中Wnt7 特异性共受体RECK是如何发挥功德克萨斯大学西南医学中心李晓淳实验室在 Cell 期刊发表了题为：Molecular basis of Wnt biogenesis, secretion and Wnt7 specific signaling 的研究论文【2】。该研究以Wnt7a的合成、分泌和激活入手，阐释了脂修饰的Wnt蛋白是如何在ER中完成由PORCN向WLS的转移，WLS如何在细胞表面释放Wnt，以及中枢神经中Wnt7 特异性共受体RECK是如何发挥功能的。为了鉴定ER中参与Wnt蛋白合成的因子，研究团队在HEK293细胞中共表达了Wnt7a-WLS-RECK复合物。电镜结构显示出一个未知内源性蛋白结合Wnt7a，质谱鉴定和AlphaFold结构预测指出该蛋白为钙网蛋白（calreticulin，CALR）。CALR的Lectin 结构域主要作用于Wnt7a 的第295位天冬酰胺糖基化修饰，此修饰位点在大部分Wnt中保守。当在Wnt7a或Wnt3a中突变掉该糖基化位点时，突变体丧失了与CALR的结合能力，同时分泌量减少，激活下游信号能力显著减弱。为了探究Wnt蛋白在被PORCN脂化时是否有CALR参与，研究团队共表达了PORCN和Wnt蛋白，CoIP实验显示，在Wnt蛋白存在的情况下，过表达的PORCN，内源WLS，内源CALR能够和Wnt蛋白形成四元复合物，加上对结构的分析，研究团队得出CALR通过稳定Wnt蛋白来帮助其从PORCN到WLS转运的结论。研究团队对其他18种Wnt蛋白进行氨基酸序列比对和CoIP实验，结果显示除了Wnt8a、Wnt8b、Wnt9a和Wnt9b，CALR参与其他15种Wnt的合成，揭示了CALR对于Wnt蛋白的折叠，转运和合成中具有重要作用。为了进一步探究Wnt蛋白是如何从WLS上释放的，研究团队又解析了单独的WLS结构。与Wnt7a-WLS复合物结构对比发现，复合物的WLS跨膜区间结合了一个磷脂分子，该结果与已经报道的Wnt8a-WLS结构（Cell 184:194）和Wnt3a-WLS结构（Nature Communications 12: 4541）类似。但是单独的WLS并没有结合磷脂分子，而且其跨膜区发生了显著的构像变化，使结合Wnt蛋白hairpin2和脂修饰的口袋闭合。另外，虽然磷脂分子没有直接参与和Wnt7a的互作，但是CoIP实验和分子动力学实验证明磷脂分子对于WLS结合Wnt7a非常重要，因此该研究首次提出由磷脂分子介导的Wnt从WLS释放模型。有趣的是，通过分析单独的WLS结构，他们发现WLS跨膜区存在一个空腔，可以作为其抑制剂的结合位点，抑制Wnt的分泌，为靶向WLS的药物设计提供了重要依据。此外，通过对Wnt7a-RECKCC4复合物结构的分析，作者发现作为Wnt7a的特异受体， RECK的CC4结构域结合在Wnt7a的N端结构域。参与RECK互作的氨基酸在其他17种Wnt蛋白里面是不保守的，突变二者相互作用的氨基酸会减弱Wnt7a介导的信号活性，从而揭示了RECK实现对Wnt7特异性的机理。 Wnt合成分泌以及Wnt7a信号通路示意图总而言之，这项工作通过结构生物学，生物化学和细胞生物学的方法鉴定了第一个Wnt合成中的伴侣蛋白，提出了Wnt合成和分泌的新模型，并且阐释了Wnt7共受体的作用。该研究为抗癌药物研发，中枢神经中血脑屏障修复提供了分子模型。