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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.

两个独立基因PKD 1和PKD 2中自然发生的突变是导致绝大多数（~99%）的常染色体显性多囊肾病（ADPKD）病例，是最常见的多囊肾病之一。遗传性疾病影响1/1000的美国人。ADPKD的标志是上皮囊肿的发展肾脏肝脏和胰腺目前还没有有效的治疗ADPKD的方法。PKD 1编码一个大的一种质膜蛋白（PKD 1或多囊蛋白1），具有较长的胞外结构域，它可以作为非典型G蛋白偶联受体发挥作用。PKD 2编码瞬时的离子通道受体电位超家族（TRPP 2、PKD 2或多囊蛋白2）。然而，这些分子的功能蛋白质和PKD 1和PKD 2突变引起ADPKD的机制尚不清楚。我们最近已经表明PKD 1和TRPP 2在质膜上形成复合物，该复合物被分泌的WNT配体。WNT蛋白直接结合PKD 1的胞外结构域并诱导Ca 2+内流和依赖于TRPP 2的全细胞电流。PKD 1/TRPP 2复合物含有Dishevelled （DVL），其是介导Wnt信号传导的细胞质蛋白。PKD 1/TRPP 2复合物具有在响应WNT配体的定向细胞迁移和趋化性中起重要作用。蛙胚胎PKD 1 与WNT 9A和DVL 2一起工作以控制肾小管直径。因此，我们假设PKD 1 和TRPP 2介导WNT诱导的Ca 2+信号传导，其对于定向细胞迁移是必需的，并有助于肾小管直径的测定。在本提案中，我们将确定WNT的机制- 诱导PKD 1/TRPP 2活化（特异性目的1）。确定WNT诱导定向细胞中的步骤 PKD 1和TRPP 2特异性影响的迁移（特异性目标2）。确定DVL是否单独或与其他与PKD 1和TRPP 2下游Wnt信号传导功能相关的胞质蛋白的关联， WNT诱导的细胞迁移（具体目标3）。这一建议有望揭示的机制， WNT诱导的PKD 1/TRPP 2活化，这些蛋白调节定向细胞的机制迁移和细胞途径激活的下游立即WNT诱导的PKD 1/TRPP 2介导的 Ca 2+信号。对这些途径的了解可以作为发现新的 ADPKD的药物靶点

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