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:9275679
- 负责人:
- 金额:$ 80.4万
- 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 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcylationBindingBinding ProteinsBiochemicalBiologyBone DiseasesCharacteristicsChemicalsComplexCongenital AbnormalityDefectDiabetes MellitusDimerizationDiseaseFamilyGoalsGrowth FactorHumanKnowledgeLigandsMalignant NeoplasmsMethodsMolecular ConformationMutateNeurodevelopmental DisorderPhosphotransferasesPlayReceptor ActivationReceptor Protein-Tyrosine KinasesReceptor SignalingRecruitment ActivityResearchResearch Project SummariesResolutionRoleSignal TransductionSignaling MoleculeSpecificityTestingTherapeuticTyrosineWNT Signaling PathwayWnt proteinsWound Healingdimerhuman diseasein vivoinsightmembernovel therapeutic interventionnovel therapeuticsreceptorreceptor bindingtherapeutic target
项目摘要
Project Summary
The research proposed in this MIRA application seeks to understand unexplored mechanisms of
transmembrane signaling across the receptor tyrosine kinase (RTK) superfamily, members of which play an
important role in human disease – from neurodevelopmental disorders, to bone diseases, cancers, diabetes,
and several congenital malformations. In the traditional view of RTK signaling, growth factor ligands induce
receptor dimers that become tyrosine autophosphorylated and recruit downstream signaling molecules. As we
understand more about the 20 different RTK families (which include 58 RTKs), however, it becomes clearer
that this view only applies to a subset of these receptors. The research proposed here focuses on two
characteristics that demand a very different mechanistic view – RTKs that bind Wnt proteins (and do not
dimerize as a result) and RTKs that have `dead' kinase or pseudokinases in their intracellular regions. New
paradigms must be understood in order to appreciate how these important receptors signal. Our goals over
the next 5-10 years are: 1. To develop a coherent picture of the role played by RTKs in Wnt signaling (which
involves 4 of the 20 RTK families), 2. To understand how RTKs with pseudokinase domains that do not even
bind ATP (found in 5 of the 20 RTK families) can signal, and 3. To determine why pseudokinases are over-
represented among the Wnt-regulated RTKs. Guided by cellular and in vivo studies of receptor/ligand
relationships we will study ligand-induced complexes biochemically, and with high-resolution structural
approaches, in order to understand in detail how Wnt protein binding leads to activation of the receptors and
co-receptors in the signaling complex. In pursuing these studies, we will investigate the role played by Wnt
acylation – requirements for which appear to be different for binding to Frizzled-family and RTK-family Wnt
receptors. We also hope to define specificity determinants in the Wnt proteins for distinct modes of signaling.
In parallel with these pursuits, we will use a structurally-guided approach, combined with chemical biology and
functional analysis of mutated receptors, to explore the mechanism of signaling by pseudokinases in the RTK
superfamily. These studies will have important implications for the 10% of the human kinome thought to be
pseudokinases, and will systematically test the hypothesis that regulated switching of pseudokinase
conformation is required for signaling. Our approaches will also bring new opportunities for therapeutic
targeting of pseudokinases such as PTK7, Ror2, and Ror1, which have been implicated in several diseases.
Together, our studies will provide important fundamental new insight into signaling by a class of receptors that
do not fit into normal paradigms for RTKs or Wnt receptors. Understanding them is crucial for deconvoluting
the complexity of Wnt signaling specificity and teasing out its multiple roles. In addition, our findings should
open new avenues for potential therapeutic inhibition – as the roles of these Wnt-binding RTKs in disease
become increasingly clear.
项目总结
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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{{ 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:
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$ 80.4万 - 项目类别:
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$ 80.4万 - 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:
$ 80.4万 - 项目类别:
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$ 80.4万 - 项目类别:
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10267847 - 财政年份:2020
- 资助金额:
$ 80.4万 - 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:
$ 80.4万 - 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:
$ 80.4万 - 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
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10598118 - 财政年份:2017
- 资助金额:
$ 80.4万 - 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
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了解通过 Ror 和 Ryk 家族受体酪氨酸激酶的 Wnt 信号传导
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