Regulation of calcium signaling by the PKD2 gene product

PKD2 基因产物对钙信号传导的调节

基本信息

批准号：
9927634
负责人：
Leonidas Tsiokas
金额：
$ 32.99万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-26 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9927634
关键词：
Address Affect American Autosomal Dominant Polycystic Kidney Binding Binding Proteins Binding Sites Biological Blood Vessels Calcium Signaling Caliber Cell Cycle Cell membrane Cell physiology Cell surface Cells Chemotaxis Complex Cytoplasmic Protein Development Embryo Epithelial cyst Extracellular Domain Fibroblasts Functional disorder G-Protein-Coupled Receptors Genes Genetic Diseases Investigation Ion Channel Kidney Knowledge Ligand Binding Ligands Light Link Liver Lymphatic Mediating Membrane Proteins Modeling Molecular Multiprotein Complexes Mutation PKD1 gene PKD2 gene PKD2 protein Pancreas Pathogenicity Pathway interactions Phase Process Proteins Rana Regulation Renal tubule structure Reporting Role Signal Transduction Stimulus TRP channel Tubular formation WNT Signaling Pathway WNT9A gene Wnt proteins Work Xenopus cell motility effective therapy extracellular gene product link protein nephrogenesis new therapeutic target novel therapeutic intervention polycystic kidney disease 1 protein programs protein function protein protein interaction receptor response spatiotemporal

项目摘要

Naturally occurring mutations in two separate genes, PKD1 and PKD2, are responsible for the vast majority (~99%) of all cases of autosomal dominant polycystic kidney disease (ADPKD), one of the most common genetic diseases affecting 1 in 1000 Americans. The hallmark of ADPKD is the development of epithelial cysts in the kidney, liver, and pancreas. Currently, there is no effective treatment for ADPKD. PKD1 encodes a large plasma membrane protein (PKD1 or Polycystin 1) with a long extracellular domain and has been speculated that it can function as an atypical G protein coupled receptor. PKD2 encodes an ion channel of the Transient Receptor Potential superfamily (TRPP2, PKD2, or Polycystin 2). However, the molecular function of these proteins and the mechanism(s) by which mutations in PKD1 and PKD2 cause ADPKD have been elusive. We have shown recently that PKD1 and TRPP2 form a complex at the plasma membrane that is activated by secreted WNT ligands. WNT proteins bind directly to the extracellular domain of PKD1 and induce Ca2+ influx and whole cell currents that are dependent on TRPP2. The PKD1/TRPP2 complex contains Dishevelleds (DVLs), which are cytoplasmic proteins that mediate Wnt signaling. The PKD1/TRPP2 complex has an essential role in directed cell migration and chemotaxis in response to a WNT ligand. In frog embryos pkd1 works together with wnt9a and dvl2 to control kidney tubular diameter. Therefore, we hypothesize that PKD1 and TRPP2 mediate WNT-induced Ca2+ signaling that is essential for directed cell migration and contributes to the determination of kidney tubule diameter. In this proposal, we will determine the mechanism of WNT- induced activation of PKD1/TRPP2 (Specific Aim 1). Determine the step(s) in WNT-induced directed cell migration specifically affected by PKD1 and TRPP2 (Specific Aim 2). Determine whether DVLs alone or in association with other cytosolic proteins linked to Wnt signaling function downstream of PKD1 and TRPP2 in WNT-induced cell migration (Specific Aim 3). This proposal is expected to shed light onto the mechanisms of WNT-induced activation of the PKD1/TRPP2, the mechanisms by which these proteins regulate directed cell migration, and cellular pathways activated immediately downstream of WNT-induced PKD1/TRPP2-mediated Ca2+ signaling. Knowledge of these pathways can be used as the springboard for the discovery of new druggable targets for ADPKD.

在两个单独的基因PKD1和PKD2中自然发生突变是绝大多数的（〜99％）在常染色体显性多囊肾病（ADPKD）中，最常见的肾脏疾病（ADPKD）之一影响1000名美国人的遗传疾病。 ADPKD的标志是上皮囊肿的发展在肾脏，肝脏和胰腺中。目前，ADPKD没有有效的治疗方法。 PKD1编码大型质膜蛋白（PKD1或Polycystin 1），具有长细胞外域，已被推测它可以充当非典型G蛋白偶联受体。 PKD2编码瞬态的离子通道受体电位超家族（TRPP2，PKD2或Polycystin 2）。但是，这些分子功能蛋白质和PKD1和PKD2引起ADPKD突变的机制难以捉摸。我们最近表明，PKD1和TRPP2在质膜处形成一个复合物，该复合物被激活分泌的Wnt配体。 Wnt蛋白直接与PKD1的细胞外结构域结合并诱导Ca2+涌入以及取决于TRPP2的全细胞电流。 PKD1/TRPP2复合物包含盘式（DVL），是介导Wnt信号传导的细胞质蛋白。 PKD1/TRPP2复合物具有响应于Wnt配体的定向细胞迁移和趋化性的重要作用。在青蛙胚胎pkd1中与WNT9A和DVL2一起工作以控制肾小管直径。因此，我们假设PKD1 TRPP2介导Wnt诱导的Ca2+信号传导，这对于定向细胞迁移至关重要，并有助于肾小管直径的测定。在此提案中，我们将确定Wnt-的机制诱导PKD1/TRPP2的激活（特定AIM 1）。确定WNT诱导的有向细胞中的步骤受PKD1和TRPP2特异性影响的迁移（特定目标2）。确定DVL是单独还是在与与Wnt信号传导功能链接到PKD1和TRPP2的其他胞质蛋白的关联 WNT诱导的细胞迁移（特定目标3）。预计该建议将阐明 Wnt诱导的PKD1/TRPP2激活，这些蛋白质调节定向细胞的机制迁移，细胞途径立即激活Wnt诱导的PKD1/TRPP2介导 CA2+信号传导。这些途径的知识可以用作发现新的跳板 ADPKD的可药物目标。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cellular Mechanisms of Ciliary Length Control.

DOI：
10.3390/cells5010006
发表时间：
2016-01-29
期刊：
Cells
影响因子：
6
作者：
Keeling J;Tsiokas L;Maskey D
通讯作者：
Maskey D

Function and regulation of TRPP2 at the plasma membrane.

DOI：
10.1152/ajprenal.90277.2008
发表时间：
2009-07
期刊：
American journal of physiology. Renal physiology
影响因子：
0
作者：
L. Tsiokas
通讯作者：
L. Tsiokas

Direct Binding between Pre-S1 and TRP-like Domains in TRPP Channels Mediates Gating and Functional Regulation by PIP2.

TRPP 通道中 Pre-S1 和 TRP 样结构域之间的直接结合介导 PIP2 的门控和功能调节。

DOI：
10.1016/j.celrep.2018.01.042
发表时间：
2018-02-06
期刊：
Cell reports
影响因子：
8.8
作者：
Zheng W;Cai R;Hofmann L;Nesin V;Hu Q;Long W;Fatehi M;Liu X;Hussein S;Kong T;Li J;Light PE;Tang J;Flockerzi V;Tsiokas L;Chen XZ
通讯作者：
Chen XZ

Nde1-mediated inhibition of ciliogenesis affects cell cycle re-entry.

DOI：
10.1038/ncb2183
发表时间：
2011-04
期刊：
Nature cell biology
影响因子：
21.3
作者：
Kim S;Zaghloul NA;Bubenshchikova E;Oh EC;Rankin S;Katsanis N;Obara T;Tsiokas L
通讯作者：
Tsiokas L

Identification and functional characterization of an N-terminal oligomerization domain for polycystin-2.

DOI：
10.1074/jbc.m803834200
发表时间：
2008-10-17
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Feng S;Okenka GM;Bai CX;Streets AJ;Newby LJ;DeChant BT;Tsiokas L;Obara T;Ong AC
通讯作者：
Ong AC