Understanding Signaling by Non-Canonical Receptor Tyrosine Kinases

了解非典型受体酪氨酸激酶的信号传导

基本信息

  • 批准号:
    10598118
  • 负责人:
  • 金额:
    $ 77.05万
  • 依托单位:
  • 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:
    2017-05-01 至 2027-04-30
  • 项目状态:
    未结题

项目摘要

The research proposed in this MIRA renewal application seeks to understand mechanisms of transmembrane signaling by members of the receptor tyrosine kinase (RTK) superfamily – and other receptor-like kinases – that do not fit the ‘rules’ that explain most RTKs. Non-canonical receptors in this group play important roles in human disease – from neurodevelopmental disorders, to bone diseases, cancers, and congenital malformations. The traditional model for RTK signaling involves ligand-induced receptor dimerization, which promotes tyrosine autophosphorylation of the receptor and recruitment of downstream signaling molecules. As we understand more about the 58 human RTKs, it has become clear that this mechanism only applies to about half of them. For example, 10% of human RTKs are linked to WNT signaling, and must function differently because their intracellular regions often have only catalytically inactive ‘pseudokinase’ domains. Still other RTKs (such as ALK) have unique extracellular regions for which ligand binding and receptor regulation are poorly understood. We have made significant progress in understanding extracellular and intracellular structures of WNT-regulated pseudokinase RTKs. Their extracellular WNT-binding modules differ significantly from their counterparts in proteins involved in ‘canonical’ WNT signaling, in ways that suggest well-defined hypotheses for how these RTKs might participate as co-receptors with Frizzled receptors in b-catenin independent WNT signaling. The intracellular pseudokinase domains of the RTKs structurally resemble the insulin receptor kinase in its ‘inactive’ conformation, and analysis of their structural dynamics suggests that they can undergo the same ‘inactive-like’ to ‘active-like’ conformational transitions seen for normal tyrosine kinase domains. Indeed, we have found that these transitions can be promoted by small molecule kinase inhibitor-like molecules, despite the fact that the isolated pseudokinase domains do not bind ATP. In the next 5-10 years of this project, we propose to test hypotheses for WNT-induced assembly of receptor complexes that incorporate pseudokinase RTKs, elucidate their specific WNT dependence and reliance on WNT acylation, gain high resolution structural views through crystallography and EM, and analyze their signaling properties. We will test hypotheses for how the pseudokinase domains contribute to signaling – either by acquiring kinase activity or by functioning as allosterically switchable interaction platforms, with precedents in other pseudokinases and in catalytically active kinases such as Aurora A. In parallel with these efforts, we will investigate new opportunities for therapeutic targeting of pseudokinase RTKs such as PTK7, ROR1, ROR2, and RYK, which have all been implicated in numerous diseases. Together, these studies will provide important new insight into signaling by receptors that do not fit normal paradigms for RTKs or WNT receptors. The new lessons should also be applicable to other classes of receptor-like kinases implicated in disease, opening new avenues for potential therapeutic inhibition.
米拉更新申请中提出的研究试图了解跨膜的机制 受体酪氨酸激酶(RTK)超家族成员和其他受体样激酶的信号- 这并不符合解释大多数RTK的“规则”。这一组中的非典型受体在 人类疾病--从神经发育障碍到骨骼疾病、癌症和先天性 畸形。传统的RTK信号模型涉及配体诱导的受体二聚化,这是 促进受体的酪氨酸自动磷酸化和下游信号分子的募集。AS 我们对58个人类RTK有了更多的了解,很明显,这个机制只适用于大约 他们中的一半。例如,10%的人类RTK连接到WNT信令,并且必须以不同的方式发挥作用 因为它们的胞内区通常只有催化不活跃的“假激酶”结构域。还有其他 RTK(如ALK)具有独特的胞外区,其配体结合和受体调节是 人们对此知之甚少。我们在理解细胞外和细胞内方面取得了重大进展 WNT调控的假激酶RTKs的结构。它们的胞外WNT结合模块明显不同 与参与WNT信号转导的蛋白质中的同种蛋白质不同,其方式表明 这些RTK如何与Frizzleed受体共同参与b-连环蛋白的假说 独立的WNT信令。RTK的细胞内假激酶结构域在结构上类似于 胰岛素受体激酶的非活性构象,对其结构动力学的分析表明 它们可以经历与正常酪氨酸相同的“类非活性”到“类活性”构象转变 激活域。事实上,我们已经发现,小分子激酶可以促进这些转变。 抑制物类分子,尽管分离的假激酶域不与ATP结合。在下一个 在这个项目的5-10年里,我们建议测试WNT诱导的受体复合体组装的假设 其结合了伪激酶RTK,阐明了它们对WNT特异性依赖和对WNT酰化的依赖, 通过结晶学和EM获得高分辨率的结构图,并分析它们的信号特性。 我们将测试假说,假性激活域是如何影响信号传递的--或者通过获取激活素 活动或作为变构可切换的交互平台,在其他 假性肌动蛋白和催化活性的肌动蛋白,如极光A。 探索PTK7、ROR1、ROR2、PTK7、ROR2、 和RYK,它们都与许多疾病有牵连。总之,这些研究将提供重要的 对RTK或WNT受体不符合正常模式的受体信号的新见解。新的 经验教训也应该适用于与疾病有关的其他类别的受体样激酶,开启了新的 潜在治疗抑制的途径。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Mark A Lemmon其他文献

Mark A Lemmon的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Mark A Lemmon', 18)}}的其他基金

Understanding how receptor tyrosine kinase activation dynamics specify proliferative cellular responses
了解受体酪氨酸激酶激活动力学如何指定增殖细胞反应
  • 批准号:
    10678825
  • 财政年份:
    2020
  • 资助金额:
    $ 77.05万
  • 项目类别:
Project 1: Improved Targeting of EGFR Family Members in Squamous Cell Carcinomas of the Head and Neck
项目 1:改进 EGFR 家族成员在头颈鳞状细胞癌中的靶向作用
  • 批准号:
    10668978
  • 财政年份:
    2020
  • 资助金额:
    $ 77.05万
  • 项目类别:
Understanding how receptor tyrosine kinase activation dynamics specify proliferative cellular responses
了解受体酪氨酸激酶激活动力学如何指定增殖细胞反应
  • 批准号:
    10263909
  • 财政年份:
    2020
  • 资助金额:
    $ 77.05万
  • 项目类别:
Project 1: Improved Targeting of EGFR Family Members in Squamous Cell Carcinomas of the Head and Neck
项目 1:改进 EGFR 家族成员在头颈鳞状细胞癌中的靶向作用
  • 批准号:
    10441508
  • 财政年份:
    2020
  • 资助金额:
    $ 77.05万
  • 项目类别:
Project 1: Improved Targeting of EGFR Family Members in Squamous Cell Carcinomas of the Head and Neck
项目 1:改进 EGFR 家族成员在头颈鳞状细胞癌中的靶向作用
  • 批准号:
    10267847
  • 财政年份:
    2020
  • 资助金额:
    $ 77.05万
  • 项目类别:
Understanding how receptor tyrosine kinase activation dynamics specify proliferative cellular responses
了解受体酪氨酸激酶激活动力学如何指定增殖细胞反应
  • 批准号:
    10400914
  • 财政年份:
    2020
  • 资助金额:
    $ 77.05万
  • 项目类别:
Understanding Signaling by Non-Canonical Receptor Tyrosine Kinases
了解非典型受体酪氨酸激酶的信号传导
  • 批准号:
    9914306
  • 财政年份:
    2017
  • 资助金额:
    $ 77.05万
  • 项目类别:
Understanding Signaling by Non-Canonical Receptor Tyrosine Kinases
了解非典型受体酪氨酸激酶的信号传导
  • 批准号:
    9275679
  • 财政年份:
    2017
  • 资助金额:
    $ 77.05万
  • 项目类别:
Understanding Signaling by Non-Canonical Receptor Tyrosine Kinases
了解非典型受体酪氨酸激酶的信号传导
  • 批准号:
    10406442
  • 财政年份:
    2017
  • 资助金额:
    $ 77.05万
  • 项目类别:
Understanding Wnt signaling through Ror and Ryk family receptor tyrosine kinases
了解通过 Ror 和 Ryk 家族受体酪氨酸激酶的 Wnt 信号传导
  • 批准号:
    9244390
  • 财政年份:
    2016
  • 资助金额:
    $ 77.05万
  • 项目类别:

相似国自然基金

帽结合蛋白(cap binding protein)调控乙烯信号转导的分子机制
  • 批准号:
    32170319
  • 批准年份:
    2021
  • 资助金额:
    58.00 万元
  • 项目类别:
    面上项目
帽结合蛋白(cap binding protein)调控乙烯信号转导的分子机制
  • 批准号:
  • 批准年份:
    2021
  • 资助金额:
    58 万元
  • 项目类别:
ID1 (Inhibitor of DNA binding 1) 在口蹄疫病毒感染中作用机制的研究
  • 批准号:
    31672538
  • 批准年份:
    2016
  • 资助金额:
    62.0 万元
  • 项目类别:
    面上项目
番茄EIN3-binding F-box蛋白2超表达诱导单性结实和果实成熟异常的机制研究
  • 批准号:
    31372080
  • 批准年份:
    2013
  • 资助金额:
    80.0 万元
  • 项目类别:
    面上项目
P53 binding protein 1 调控乳腺癌进展转移及化疗敏感性的机制研究
  • 批准号:
    81172529
  • 批准年份:
    2011
  • 资助金额:
    58.0 万元
  • 项目类别:
    面上项目
DBP(Vitamin D Binding Protein)在多发性硬化中的作用和相关机制的蛋白质组学研究
  • 批准号:
    81070952
  • 批准年份:
    2010
  • 资助金额:
    35.0 万元
  • 项目类别:
    面上项目
研究EB1(End-Binding protein 1)的癌基因特性及作用机制
  • 批准号:
    30672361
  • 批准年份:
    2006
  • 资助金额:
    24.0 万元
  • 项目类别:
    面上项目

相似海外基金

Collaborative Research: NSF-BSF: How cell adhesion molecules control neuronal circuit wiring: Binding affinities, binding availability and sub-cellular localization
合作研究:NSF-BSF:细胞粘附分子如何控制神经元电路布线:结合亲和力、结合可用性和亚细胞定位
  • 批准号:
    2321481
  • 财政年份:
    2024
  • 资助金额:
    $ 77.05万
  • 项目类别:
    Continuing Grant
Collaborative Research: NSF-BSF: How cell adhesion molecules control neuronal circuit wiring: Binding affinities, binding availability and sub-cellular localization
合作研究:NSF-BSF:细胞粘附分子如何控制神经元电路布线:结合亲和力、结合可用性和亚细胞定位
  • 批准号:
    2321480
  • 财政年份:
    2024
  • 资助金额:
    $ 77.05万
  • 项目类别:
    Continuing Grant
Alkane transformations through binding to metals
通过与金属结合进行烷烃转化
  • 批准号:
    DP240103289
  • 财政年份:
    2024
  • 资助金额:
    $ 77.05万
  • 项目类别:
    Discovery Projects
NPBactID - Differential binding of peptoid functionalized nanoparticles to bacteria for identifying specific strains
NPBactID - 类肽功能化纳米粒子与细菌的差异结合,用于识别特定菌株
  • 批准号:
    EP/Y029542/1
  • 财政年份:
    2024
  • 资助金额:
    $ 77.05万
  • 项目类别:
    Fellowship
Conformations of musk odorants and their binding to human musk receptors
麝香气味剂的构象及其与人类麝香受体的结合
  • 批准号:
    EP/X039420/1
  • 财政年份:
    2024
  • 资助金额:
    $ 77.05万
  • 项目类别:
    Research Grant
Postdoctoral Fellowship: OPP-PRF: Understanding the Role of Specific Iron-binding Organic Ligands in Governing Iron Biogeochemistry in the Southern Ocean
博士后奖学金:OPP-PRF:了解特定铁结合有机配体在控制南大洋铁生物地球化学中的作用
  • 批准号:
    2317664
  • 财政年份:
    2024
  • 资助金额:
    $ 77.05万
  • 项目类别:
    Standard Grant
I-Corps: Translation Potential of Real-time, Ultrasensitive Electrical Transduction of Biological Binding Events for Pathogen and Disease Detection
I-Corps:生物结合事件的实时、超灵敏电转导在病原体和疾病检测中的转化潜力
  • 批准号:
    2419915
  • 财政年份:
    2024
  • 资助金额:
    $ 77.05万
  • 项目类别:
    Standard Grant
The roles of a universally conserved DNA-and RNA-binding domain in controlling MRSA virulence and antibiotic resistance
普遍保守的 DNA 和 RNA 结合域在控制 MRSA 毒力和抗生素耐药性中的作用
  • 批准号:
    MR/Y013131/1
  • 财政年份:
    2024
  • 资助金额:
    $ 77.05万
  • 项目类别:
    Research Grant
CRII: OAC: Development of a modular framework for the modeling of peptide and protein binding to membranes
CRII:OAC:开发用于模拟肽和蛋白质与膜结合的模块化框架
  • 批准号:
    2347997
  • 财政年份:
    2024
  • 资助金额:
    $ 77.05万
  • 项目类别:
    Standard Grant
How lipid binding proteins shape the activity of nuclear hormone receptors
脂质结合蛋白如何影响核激素受体的活性
  • 批准号:
    DP240103141
  • 财政年份:
    2024
  • 资助金额:
    $ 77.05万
  • 项目类别:
    Discovery Projects
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了