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:10400914
- 负责人:
- 金额:$ 51.82万
- 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 valueSpecificityT-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.
项目概要
我们建议结合生物物理成像和生化方法来解决两个尚未解答的关键问题
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:
一个。什么定义了特定 RTK 下游的不同反应集和细胞命运?
b.给定 RTK 的不同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)促进细胞增殖和增殖。
分别通过 EGFR 和 TrkA 在 PC12 细胞中进行分化反应,显然使用同一组
信号通路。早期研究表明 Erk 激活动力学在确定
这些配体诱导不同的细胞命运,短暂的 Erk 激活与增殖相关
并通过分化持续激活 Erk。而不是仅仅由不同的反馈“线路”来定义
在细胞内 MAP 激酶级联中,我们和其他人发现 RTK 激活动力学发挥着重要作用
在定义信令网络的动态属性方面发挥着直接作用。最近的几项研究进一步认为
配体诱导的 RTK 二聚体的强度(和/或它们的寿命)决定了信号特异性,提供了
RTK 信号中动态确定偏向激动的可能性。
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
以不同方式激活相同 RTK 细胞内区域如何导致显着不同的细胞
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
信号传导结果由 RTK 二聚体稳定性和动态决定的假设。使用完整和
嵌合受体,我们将通过询问改变 RTK 二聚化动力学如何影响来检验这个假设
受体内吞作用、内吞后运输以及下游信号网络的动态。我们
将 RTK 运输的单分子成像和显微镜研究与质谱分析相结合
对下游信号网络的生化研究,以获得对此的综合了解。我们的小学
动机是研究修改 RTK 信号动态(而不是简单地抑制 RTK)如何可能
可用于未来的癌症治疗方法。我们的具体目标解决以下问题:
1 相同的 RTK 细胞内区域如何根据其不同的方式引发正交细胞反应
活性?
2 不同神经调节蛋白 (NRG) 配体诱导的 ErbB4/HER4 二聚体的寿命是多少?
他们持续发出信号的基础是什么?
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 T 细胞受体的动力学校对。
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)
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:
$ 51.82万 - 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:
$ 51.82万 - 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:
$ 51.82万 - 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:
$ 51.82万 - 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:
$ 51.82万 - 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:
$ 51.82万 - 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:
$ 51.82万 - 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:
$ 51.82万 - 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:
$ 51.82万 - 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:
$ 51.82万 - 项目类别:
相似海外基金
Discovery of a High Affinity, Selective and β-arrestin Biased 5-HT7R Agonist
发现高亲和力、选择性和β-抑制蛋白偏向的 5-HT7R 激动剂
- 批准号:
10412227 - 财政年份:2022
- 资助金额:
$ 51.82万 - 项目类别:
Discovery of a High Affinity, Selective and β-arrestin Biased 5-HT7R Agonist
发现高亲和力、选择性和β-抑制蛋白偏向的 5-HT7R 激动剂
- 批准号:
10610473 - 财政年份:2022
- 资助金额:
$ 51.82万 - 项目类别:
Supplement to Discovery of a high affinity, selective and beta-arrestinbiased 5-HT7R Agonist Grant
对高亲和力、选择性和 β 抑制偏向 5-HT7R 激动剂发现的补充补助金
- 批准号:
10799162 - 财政年份:2022
- 资助金额:
$ 51.82万 - 项目类别:
NMDA RECEPTOR--AGONIST AFFINITY, EFFICACY/TRANSDUCTION
NMDA 受体——激动剂亲和力、功效/转导
- 批准号:
6639179 - 财政年份:2001
- 资助金额:
$ 51.82万 - 项目类别:
NMDA RECEPTOR--AGONIST AFFINITY, EFFICACY/TRANSDUCTION
NMDA 受体——激动剂亲和力、功效/转导
- 批准号:
6724797 - 财政年份:2001
- 资助金额:
$ 51.82万 - 项目类别:
General Anesthetics and nAcCHOR Agonist Affinity
全身麻醉药和 nAcCHOR 激动剂亲和力
- 批准号:
6636512 - 财政年份:2001
- 资助金额:
$ 51.82万 - 项目类别:
General Anesthetics and nAcCHOR Agonist Affinity
全身麻醉药和 nAcCHOR 激动剂亲和力
- 批准号:
6326889 - 财政年份:2001
- 资助金额:
$ 51.82万 - 项目类别:
NMDA RECEPTOR--AGONIST AFFINITY, EFFICACY/TRANSDUCTION
NMDA 受体——激动剂亲和力、功效/转导
- 批准号:
6266928 - 财政年份:2001
- 资助金额:
$ 51.82万 - 项目类别:
NMDA RECEPTOR--AGONIST AFFINITY, EFFICACY/TRANSDUCTION
NMDA 受体——激动剂亲和力、功效/转导
- 批准号:
6539099 - 财政年份:2001
- 资助金额:
$ 51.82万 - 项目类别:
General Anesthetics and nAcCHOR Agonist Affinity
全身麻醉药和 nAcCHOR 激动剂亲和力
- 批准号:
6520329 - 财政年份:2001
- 资助金额:
$ 51.82万 - 项目类别: