Role of LMTK2 in CFTR Trafficking

LMTK2 在 CFTR 贩运中的作用

基本信息

项目摘要

Cystic fibrosis (CF) is a lethal genetic disease that afflicts some 30,000 individuals in the United States alone. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, that encodes for a chloride selective anion channel. CFTR is expressed in the apical membranes of polarized epithelial cells lining the airways and gastrointestinal tract, where it is responsible for regulating salt and water transport. The most common mutation in CF is caused by the deletion of a phenylalanine residue at position 508 (¿F508) in CFTR. Expression of ¿F508 CFTR at the cell surface is negligible because ¿F508 CFTR is not exported efficiently from the endoplasmic reticulum and because the half-life of ¿F508 protein that does reach the plasma membrane is severely reduced. The reduced cell surface stability of ¿F508 CFTR appears to be due to the inability of endocytosed ¿F508 CFTR to appropriately recycle back to the plasma membrane. The mechanisms and protein interactions that control the recycling of internalized CFTR are not known. Despite the many publications on CFTR trafficking, nearly all studies have been performed using non- physiological expression systems such as fibroblasts. Although these systems have proven easy to manipulate, their ease of use has been at the expense of physiological relevance. Critical to our present studies is the choice of relevant model epithelial cells and tissues. However, little is known about CFTR recycling in polarized epithelial tissues. Lack of such knowledge is an important problem, since without it, the ability to maintain therapeutically beneficial levels of ¿F508 CFTR at the cell surface solely through pharmacological manipulation of the biosynthetic pathway is unlikely. We have recently discovered that LMTK2, a membrane tethered kinase associated with early endosomes, is critical to directing internalized CFTR to the recycling pathway. The focus of our present application is based on three seminal observations; 1) CFTR is a substrate for LMTK2 kinase activity; (2) lack of LMTK2 activity leads to loss of CFTR recycling and a loss of functional CFTR from the cell surface; and (3) overexpression of LMTK2 leads to enhanced CFTR recycling and an increase in cell surface CFTR. The overall hypothesis to be tested in this proposal is that LMTK2 is a critical regulator in the endocytic recycling of CFTR. To test this hypothesis, we propose three specific aims that not only seek to characterize the role of LMTK2 in regulating CFTR trafficking, but also seek to identify a mechanistic basis for our observations. We are confident that elucidation of the mechanisms involved in CFTR trafficking will provide novel therapeutic targets for enhancing ¿F508 CFTR recycling in a therapeutically beneficial manner. In addition, we are certain that our proposed studies will provide important and novel insights not only into CFTR biology, but also into mechanisms of protein recycling.
囊性纤维化(CF)是一种致命的遗传性疾病,仅在美国就有大约30,000人受到影响。 CF是由囊性纤维化跨膜传导调节因子(CFTR)基因突变引起的, 编码氯离子选择性阴离子通道。CFTR表达于极化细胞的顶膜, 上皮细胞排列在气道和胃肠道,负责调节盐和水 运输CF中最常见的突变是由于在第111位的苯丙氨酸残基缺失引起的。 508(<$F508)在CFTR。在细胞表面的<$F508 CFTR表达可以忽略不计,因为<$F508 CFTR是 不能有效地从内质网中输出,并且因为F508蛋白的半衰期 到达质膜的能力严重降低。F508 CFTR的细胞表面稳定性降低, 这是由于内吞的F508 CFTR不能适当地再循环回质膜。 控制内化CFTR再循环的机制和蛋白质相互作用尚不清楚。 尽管有许多关于CFTR贩运的出版物,但几乎所有的研究都是使用非 生理表达系统如成纤维细胞。虽然这些系统已被证明易于 由于无法操纵,它们的易用性是以牺牲生理相关性为代价的。对我们现在至关重要 研究的重点是选择相关的上皮细胞和组织模型。然而,人们对CFTR知之甚少 极化上皮组织中的再循环。缺乏这种知识是一个重要问题,因为没有这种知识, 仅通过以下方式在细胞表面维持治疗有益水平的F508 CFTR的能力: 生物合成途径的药理学操作是不可能的。我们最近发现, LMTK 2是一种与早期核内体相关的膜系激酶,对引导内化至关重要。 CFTR到回收途径。本申请的焦点基于三个开创性的观察: 1)CFTR是LMTK 2激酶活性的底物;(2)LMTK 2活性的缺乏导致CFTR再循环的丧失 和细胞表面功能性CFTR的丧失;和(3)LMTK 2的过表达导致增强的 CFTR再循环和细胞表面CFTR的增加。本提案中要检验的总体假设是 LMTK 2是CFTR的内吞再循环中的关键调节剂。为了验证这一假设,我们建议 三个具体目标,不仅试图描述LMTK 2在管制CFTR贩运方面的作用, 试图为我们的观察找到一个机械的基础。我们相信,阐明这些机制 参与CFTR贩运将提供新的治疗靶点,以增强CF 508 CFTR的再循环, 治疗有益的方式。此外,我们相信,我们拟议的研究将提供重要的 和新的见解,不仅对CFTR生物学,而且对蛋白质回收机制。

项目成果

期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Lemur Tyrosine Kinase 2, a novel target in prostate cancer therapy.
  • DOI:
    10.18632/oncotarget.3899
  • 发表时间:
    2015-06-10
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Shah K;Bradbury NA
  • 通讯作者:
    Bradbury NA
Natural Compounds as Therapeutic Agents in the Treatment Cystic Fibrosis.
天然化合物作为治疗囊性纤维化的治疗剂。
Evidence against resveratrol as a viable therapy for the rescue of defective ΔF508 CFTR.
  • DOI:
    10.1016/j.bbagen.2015.08.020
  • 发表时间:
    2015-11
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Jai Y;Shah K;Bridges RJ;Bradbury NA
  • 通讯作者:
    Bradbury NA
Signal dependent ER export of lemur tyrosine kinase 2.
狐猴酪氨酸激酶 2 信号依赖性 ER 输出。
  • DOI:
    10.1186/s12860-015-0072-6
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Butler,EC;Bradbury,NeilA
  • 通讯作者:
    Bradbury,NeilA
Kinase modulation of androgen receptor signaling: implications for prostate cancer.
  • DOI:
    10.14800/ccm.1023
  • 发表时间:
    2015-01-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Shah, Kalpit;Bradbury, Neil A
  • 通讯作者:
    Bradbury, Neil A
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Neil A Bradbury其他文献

Neil A Bradbury的其他文献

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{{ truncateString('Neil A Bradbury', 18)}}的其他基金

Role of LMTK2 in CFTR Trafficking
LMTK2 在 CFTR 贩运中的作用
  • 批准号:
    8197503
  • 财政年份:
    2010
  • 资助金额:
    $ 37.73万
  • 项目类别:
Role of LMTK2 in CFTR Trafficking
LMTK2 在 CFTR 贩运中的作用
  • 批准号:
    8039716
  • 财政年份:
    2010
  • 资助金额:
    $ 37.73万
  • 项目类别:
Role of LMTK2 in CFTR Trafficking
LMTK2 在 CFTR 贩运中的作用
  • 批准号:
    8386586
  • 财政年份:
    2010
  • 资助金额:
    $ 37.73万
  • 项目类别:
Functional expression of CFTR and other multidomain proteins
CFTR 和其他多域蛋白的功能表达
  • 批准号:
    7904914
  • 财政年份:
    2009
  • 资助金额:
    $ 37.73万
  • 项目类别:
Functional expression of CFTR and other multidomain proteins
CFTR 和其他多域蛋白的功能表达
  • 批准号:
    7739851
  • 财政年份:
    2009
  • 资助金额:
    $ 37.73万
  • 项目类别:
CFTR REGULATION BY TARGETED KINASE AND PHOSPHATASE
靶向激酶和磷酸酶对 CFTR 的调节
  • 批准号:
    6654123
  • 财政年份:
    2002
  • 资助金额:
    $ 37.73万
  • 项目类别:
Mechanisms of CFTR Internalization
CFTR 内部化机制
  • 批准号:
    6371117
  • 财政年份:
    2001
  • 资助金额:
    $ 37.73万
  • 项目类别:
Mechanisms of CFTR Internalization
CFTR 内部化机制
  • 批准号:
    6788292
  • 财政年份:
    2001
  • 资助金额:
    $ 37.73万
  • 项目类别:
Mechanisms of CFTR Internalization
CFTR 内部化机制
  • 批准号:
    6524255
  • 财政年份:
    2001
  • 资助金额:
    $ 37.73万
  • 项目类别:
CFTR REGULATION BY TARGETED KINASE AND PHOSPHATASE
靶向激酶和磷酸酶对 CFTR 的调节
  • 批准号:
    6499598
  • 财政年份:
    2001
  • 资助金额:
    $ 37.73万
  • 项目类别:

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