Probing tyrosine phosphatase structure and function
探究酪氨酸磷酸酶的结构和功能
基本信息
- 批准号:10437738
- 负责人:
- 金额:$ 39.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AnimalsAreaBiochemicalBiochemistryBiologicalBiological ProcessBiologyCell physiologyCellsDevelopmentDiseaseDrug TargetingDrug resistanceEnzymesGoalsHumanKnowledgeLabelMalignant NeoplasmsMapsMass Spectrum AnalysisMethodsMolecularMutateMutationPTPN11 genePhenotypePhosphoric Monoester HydrolasesPlayPoint MutationPost-Translational Protein ProcessingProtein Tyrosine KinaseProtein Tyrosine PhosphataseProteinsRegulationResearchRoleSignal TransductionStructureT-LymphocyteTechniquesTherapeuticTyrosineTyrosine PhosphorylationWorkbiochemical toolscell typeexperimental studyhuman diseaseimmune activationinterestmutation screeningnovel strategiespreferenceresistance mutationtargeted cancer therapytargeted treatmenttool
项目摘要
PROJECT SUMMARY
The enzymatic modification of proteins through tyrosine phosphorylation is a common mechanism
for relaying information in animal cells. Tyrosine kinases act in a signal-responsive manner to
phosphorylate specific proteins at tyrosine residues, and the opposing tyrosine phosphatases
dephosphorylate proteins to dynamically regulate signals. Tyrosine phosphorylation is essential to many
biological processes in healthy cells, and the dysregulation of tyrosine phosphorylation is a common
feature of many diseases, most notably cancers. Over the past few decades, we have developed an
extensive understanding of tyrosine kinase function and regulation, but our knowledge of tyrosine
phosphatases lags behind. This disparity is partly due to the fact that it is easier to develop drugs that
target tyrosine kinases than tyrosine phosphatases, and the therapeutic potential of tyrosine kinases has
motivated the development of robust tools to study their structure, biochemistry, and biology.
The overarching goals of my lab are to understand, at the molecular level, how tyrosine
phosphatases select substrate proteins to dephosphorylate, how they are regulated through dynamic
changes in their structure, and how they contribute to healthy and disease-associated signaling. Over
the next five years, my group will devise new techniques to study tyrosine phosphatases. We are currently
developing a high-throughput biochemical platform to rapidly identify and compare the substrate
sequence preferences of tyrosine phosphatases. These analyses will be conducted in parallel with
proximity-labeling experiments in live cells to tag the interaction partners of tyrosine phosphatases for
identification by mass spectrometry. Together, these approaches will allow us to map the substrates of
tyrosine phosphatases and help define the signaling roles of these enzymes. We are also developing
methods to rapidly characterize the functional effects of all possible point mutations in a tyrosine
phosphatase. These mutational screens will allow us to identify new modes of regulation, pinpoint the
functional consequences of disease-associated mutations, and map likely drug-resistance mutations that
may arise to phosphatase-targeted cancer therapies.
We are broadly interested in two areas of signaling biology: diseases where tyrosine
phosphatases are mutated and/or dysregulated, and the activation of immune T cells. As we develop
new biochemical tools, we will initially apply these tools to the tyrosine phosphatase SHP2, which plays
a causal role in several congenital diseases and cancers, and is also critical to normal signaling in many
cell types, including T cells. Our work will clarify the signaling functions of SHP2, connect known
mutations to specific phenotypes, and help guide the development of SHP2-targeted therapies. In the
long-term, we will apply our novel approaches to other tyrosine phosphatases.
项目摘要
通过酪氨酸磷酸化对蛋白质进行酶促修饰是一种常见的机制
在动物细胞中传递信息。酪氨酸激酶以信号响应的方式作用于
在酪氨酸残基磷酸化特定蛋白质,和相反的酪氨酸磷酸酶
使蛋白质去磷酸化以动态调节信号。酪氨酸磷酸化对许多人来说至关重要
在健康细胞中,酪氨酸磷酸化的失调是一种常见的生物学过程。
许多疾病的特征,尤其是癌症。在过去的几十年里,我们开发了一种
酪氨酸激酶的功能和调节的广泛理解,但我们的知识酪氨酸
磷酸酶滞后。这种差异部分是由于开发药物更容易,
靶向酪氨酸激酶而不是酪氨酸磷酸酶,酪氨酸激酶的治疗潜力
激发了强大的工具来研究它们的结构,生物化学和生物学的发展。
我实验室的首要目标是在分子水平上了解酪氨酸
磷酸酶选择底物蛋白去磷酸化,它们如何通过动态调节
它们结构的变化,以及它们如何促进健康和疾病相关的信号传导。超过
在接下来的五年里,我的小组将设计新的技术来研究酪氨酸磷酸酶。我们目前正在
开发高通量生物化学平台以快速鉴定和比较底物
酪氨酸磷酸酶的序列偏好。这些分析将与下列项目同时进行:
在活细胞中进行邻近标记实验,以标记酪氨酸磷酸酶的相互作用伴侣,
质谱鉴定。总之,这些方法将使我们能够绘制出
酪氨酸磷酸酶和帮助确定这些酶的信号作用。我们也在开发
快速表征酪氨酸中所有可能的点突变的功能效应的方法
磷酸酶。这些突变筛选将使我们能够识别新的调控模式,
疾病相关突变的功能后果,并绘制可能的耐药性突变,
磷酸酶靶向癌症治疗的可能性。
我们对信号生物学的两个领域广泛感兴趣:
磷酸酶突变和/或失调,以及免疫T细胞的活化。在我们的发展过程中
新的生物化学工具,我们将首先将这些工具应用于酪氨酸磷酸酶SHP 2,它发挥
在几种先天性疾病和癌症中起因果作用,对许多疾病的正常信号传导也至关重要。
细胞类型,包括T细胞。我们的工作将阐明SHP 2的信号功能,连接已知的
突变的特定表型,并帮助指导SHP 2靶向治疗的发展。在
从长远来看,我们将把我们的新方法应用于其他酪氨酸磷酸酶。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Neel H Shah其他文献
Neel H Shah的其他文献
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{{ truncateString('Neel H Shah', 18)}}的其他基金
A Generalizable Photo-Crosslinking Strategy to Identify Tyrosine Phosphatase Substrates
识别酪氨酸磷酸酶底物的通用光交联策略
- 批准号:
10612641 - 财政年份:2023
- 资助金额:
$ 39.3万 - 项目类别:
Probing tyrosine phosphatase structure and function
探究酪氨酸磷酸酶的结构和功能
- 批准号:
10384782 - 财政年份:2020
- 资助金额:
$ 39.3万 - 项目类别:
Probing tyrosine phosphatase structure and function
探究酪氨酸磷酸酶的结构和功能
- 批准号:
10201679 - 财政年份:2020
- 资助金额:
$ 39.3万 - 项目类别:
Probing tyrosine phosphatase structure and function
探究酪氨酸磷酸酶的结构和功能
- 批准号:
10688703 - 财政年份:2020
- 资助金额:
$ 39.3万 - 项目类别:
Probing tyrosine phosphatase structure and function
探究酪氨酸磷酸酶的结构和功能
- 批准号:
10027894 - 财政年份:2020
- 资助金额:
$ 39.3万 - 项目类别:
Probing tyrosine phosphatase structure and function
探究酪氨酸磷酸酶的结构和功能
- 批准号:
10876718 - 财政年份:2020
- 资助金额:
$ 39.3万 - 项目类别:
Probing tyrosine phosphatase structure and function
探究酪氨酸磷酸酶的结构和功能
- 批准号:
10661587 - 财政年份:2020
- 资助金额:
$ 39.3万 - 项目类别:
Probing tyrosine phosphatase structure and function
探究酪氨酸磷酸酶的结构和功能
- 批准号:
10393278 - 财政年份:2020
- 资助金额:
$ 39.3万 - 项目类别:
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