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
基本信息
- 批准号:10263909
- 负责人:
- 金额:$ 52.88万
- 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:2020-09-15 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffinityAgonistBiochemicalBiological AssayBiophysicsBreast Cancer cell lineCell ProliferationCellsCessation of lifeChimera organismDataDimerizationEndocytosisEpidermal Growth FactorEpidermal Growth Factor ReceptorEpiregulinErbB4 geneFeedbackFutureG-Protein-Coupled ReceptorsGoalsImageKineticsLigandsMAP Kinase ModulesMalignant NeoplasmsMass Spectrum AnalysisMeasuresMethodsMicroscopyMotivationMutationNatureNerve Growth FactorsNeuregulinsNeurotrophic Tyrosine Kinase Receptor Type 1OncogenicOutcomePC12 CellsPathway interactionsPharmacologyPhosphorylation SitePlayPropertyReceptor ActivationReceptor Protein-Tyrosine KinasesReceptor SignalingResistanceRoleSignal PathwaySignal TransductionSpecific qualifier valueSpecificityStructureT-Cell ReceptorTestingTherapeuticTransducersWorkbasecancer celldesigndimerepigeninsightmolecular imagingnetwork modelsreceptorresponsesingle moleculetargeted treatmenttherapeutic targettrafficking
项目摘要
Project Summary
We propose to combine biophysical imaging and biochemical approaches to address two key unanswered
questions in the field of signaling by receptor tyrosine kinases (RTKs) – a principal class of therapeutic targets
in cancer where resistance to current therapies necessitates new pharmacological approaches:
a. What defines the distinct set of responses, and cell fate, downstream of a particular RTK?
b. How can different ligands for a given RTK promote distinct cellular responses?
It is well known that epidermal growth factor (EGF) and nerve growth factor (NGF) promote proliferative and
differentiative responses respectively in PC12 cells, through EGFR and TrkA, apparently using the same set of
signaling pathways. Early studies showed that Erk activation kinetics plays a key role in determining the
different cell fates induced by these ligands, with transient Erk activation being associated with proliferation
and sustained Erk activation with differentiation. Rather than being defined solely by different feedback ‘wiring’
in the intracellular MAP kinase cascade, we and others have found that the RTK activation kinetics play a
direct role in defining the dynamic properties of the signaling network. Several recent studies further argue that
the strength of ligand-induced RTK dimers (and/or their lifetime) dictates signaling specificity, offering the
possibility of dynamically-determined biased agonism in RTK signaling.
To gain insight into the mechanistic basis for biased agonism in RTK signaling, we propose to elucidate
how activating the same RTK intracellular region in different ways can result in dramatically different cellular
responses (proliferation vs differentiation). Our previous structural, biophysical, and biochemical data suggest
the hypothesis that signaling outcome is determined by RTK dimer stability and dynamics. Using intact and
chimeric receptors, we will test this hypothesis by asking how altering RTK dimerization kinetics influences
receptor endocytosis, post-endocytic trafficking, and dynamics of the downstream signaling network. We
combine single-molecule imaging and microscopy studies of RTK trafficking with mass spectrometry and
biochemical studies of downstream signaling networks to yield an integrated picture of this. Our primary
motivation is to investigate how modifying RTK signaling dynamics (rather than simply inhibiting RTKs) might
be used in future therapeutic approaches in cancer. Our Specific Aims address the following questions:
1 How can the same RTK intracellular region elicit orthogonal cellular responses depending on how it is
activated?
2 What are the lifetimes of ErbB4/HER4 dimers induced by different neuregulin (NRG) ligands, and what is
the basis for their sustained signaling?
Our overall goal is to understand how dimerization dynamics can define signaling specificity, possibly through
a kinetic proofreading similar to that seen in the T-cell receptor.
项目摘要
我们建议将联合收割机生物物理成像和生物化学方法相结合,以解决两个关键的悬而未决的问题
受体酪氨酸激酶(RTK)信号传导领域的问题--一类主要的治疗靶点
在对当前疗法产生耐药性的癌症中,需要新的药理学方法:
a.什么定义了一个特定RTK下游的不同反应集和细胞命运?
B.不同的RTK配体如何促进不同的细胞反应?
众所周知,表皮生长因子(EGF)和神经生长因子(NGF)促进细胞增殖和分化。
分化反应分别在PC 12细胞,通过EGFR和TrkA,显然使用同一套
信号通路早期的研究表明,Erk激活动力学在决定细胞凋亡中起着关键作用。
这些配体诱导的不同细胞命运,瞬时Erk活化与增殖相关
并伴随分化持续激活ERK。而不是仅仅由不同的反馈“线路”来定义
在细胞内MAP激酶级联反应中,我们和其他人已经发现RTK激活动力学起作用,
在定义信令网络的动态特性中的直接作用。最近的几项研究进一步指出,
配体诱导的RTK二聚体的强度(和/或它们的寿命)决定了信号传导特异性,
RTK信号传导中动态确定的偏向激动的可能性。
为了深入了解RTK信号传导中偏向激动的机制基础,我们建议阐明
如何以不同的方式激活相同的RTK细胞内区域可以导致显著不同的细胞
反应(增殖与分化)。我们之前的结构生物物理和生化数据表明
信号转导结果由RTK二聚体稳定性和动力学决定的假设。使用完整的和
嵌合受体,我们将测试这一假设,询问如何改变RTK二聚化动力学影响
受体内吞作用、内吞后运输和下游信号网络的动力学。我们
联合收割机将RTK运输的单分子成像和显微镜研究与质谱法结合起来,
下游信号网络的生物化学研究,以产生一个完整的图片。我们的首要
动机是研究如何修改RTK信号动力学(而不是简单地抑制RTK)可能
用于未来的癌症治疗方法。我们的具体目标解决了以下问题:
1相同的RTK细胞内区域如何引起正交的细胞反应,这取决于它是如何
激活?
2不同的神经调节蛋白(NRG)配体诱导的ErbB 4/HER 4二聚体的寿命是多少?
它们持续发出信号的基础
我们的总体目标是了解二聚化动力学如何定义信号特异性,可能通过
类似于在T细胞受体中看到的动力学校正。
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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Mark A Lemmon其他文献
Mark A Lemmon的其他文献
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{{ 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:
$ 52.88万 - 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:
$ 52.88万 - 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:
$ 52.88万 - 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:
$ 52.88万 - 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:
$ 52.88万 - 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:
$ 52.88万 - 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:
10598118 - 财政年份:2017
- 资助金额:
$ 52.88万 - 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:
$ 52.88万 - 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:
$ 52.88万 - 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:
$ 52.88万 - 项目类别:
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