Role of spectrin signaling complex in angiogenesis
血影蛋白信号复合物在血管生成中的作用
基本信息
- 批准号:10301004
- 负责人:
- 金额:$ 30.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-01 至 2022-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressBiochemicalBlood VesselsC-terminalCellsCharacteristicsClinicalComplexConsensusCytoskeletonDataDevelopmentDiseaseDown-RegulationEmbryoEndothelial CellsEndotheliumEnzymesEquilibriumExhibitsFailureFunctional disorderHeartInflammatoryInterventionKDR geneKnowledgeMalignant - descriptorMalignant NeoplasmsMediatingMediator of activation proteinMembraneMolecularMolecular ChaperonesMusMutant Strains MiceNeoplasm MetastasisNervous system structureNewborn InfantPathogenesisPathologicPathway interactionsPatternPhenotypePhosphorylationPhosphorylation SitePositioning AttributeProcessProliferatingPropertyProtein Tyrosine PhosphataseProtein-Serine-Threonine KinasesProteinsReceptor SignalingRegulationResistanceRetinaRetinal DiseasesRoleScaffolding ProteinSerineSerine/Threonine PhosphorylationSignal PathwaySignal TransductionSiteSpecificitySpectrinStructure of beta Cell of isletSystemTestingTherapeuticThreonineToxic effectTyrosine PhosphorylationUbiquitinationVascular Endothelial CellVascular Endothelial Growth FactorsVegf InhibitorWorkZebrafishangiogenesisantagonistbasebetaIV spectrincalmodulin-dependent protein kinase IIcell typein vivoinsightmaculamutantnew therapeutic targetnovelreceptorspatiotemporaltissue repairtraffickingtumor growthubiquitin ligase
项目摘要
Defective angiogenesis underlies the pathogenesis of over 50 malignant, ischemic and inflammatory diseases.
While current antagonists of VEGF signaling have a wide range of therapeutic applications, most of these
treatments fail to provide long-term efficacy due to acquired resistance and toxicities. Overcoming these
clinical challenges will therefore require addressing a number of critical aspects of VEGF signaling that are
very much unclear. VEGFR2 is the principal driver of sprouting angiogenesis as its membrane trafficking
controls the specificity, duration and amplitude of many, if not most, of the VEGF-induced signaling pathways.
But unlike the molecular basis of VEGFR2 tyrosine phosphorylation that transduces receptor signaling, how its
membrane trafficking and turnover are spatiotemporally coordinated by various serine/threonine kinases,
chaperones and ubiquitin ligases remain poorly understood. In fact, although PKCs have been long recognized
as key mediators of VEGFR2 degradation, it is still unclear whether PKCs directly or indirectly promote
serine/threonine phosphorylation-induced turnover. Here our work supports an exciting new mechanism by
which VEGFR2 stability is regulated through a novel membrane-based signaling complex. In preliminary
studies, we discovered that IV-spectrin, a large membrane cytoskeletal scaffolding protein characterized only
in the nervous system and heart, is expressed in vascular endothelial cells (ECs) to act as a critical negative
regulator of angiogenesis. IV-spectrin dysfunction in newborn mice and zebrafish embryos produce debilitating
hypersprouting vessels in part due to abnormally high levels of VEGF/VEGFR2 signaling and dramatically
elevated number of tip cells. Our data strongly suggest that IV-spectrin functions as a crucial signaling
platform by which VEGFR2 is targeted for degradation through direct CaMKII-induced phosphorylation of novel
serine/threonine sites. Based on our findings, we hypothesize that the IV-spectrin/CaMKII signaling complex
regulates VEGFR2 phosphorylation, membrane trafficking and turnover to suppress VEGF signaling and tip
cell phenotype during sprouting angiogenesis. Two aims are proposed to test this hypothesis: 1) Define IV-
spectrin-based mechanisms of VEGF signaling during sprouting angiogenesis; 2) Establish the role of IV-
spectrin in endothelial tip and stalk cell specification. Collectively, results from these studies will address a
crucial question in VEGFR signaling through the characterization of a novel IV-spectrin signaling complex, and
identify new vascular targets in failed long-term VEGF-related therapies.
缺陷性血管生成是50多种恶性、缺血性和炎性疾病的发病机制的基础。
虽然目前VEGF信号传导的拮抗剂具有广泛的治疗应用,但这些拮抗剂中的大多数都是抗肿瘤的。
由于获得性抗性和毒性,治疗不能提供长期功效。克服这些
因此,临床挑战需要解决VEGF信号传导的许多关键方面,
非常不清楚。VEGFR 2作为其膜运输是萌芽血管生成的主要驱动力
控制许多(如果不是大多数)VEGF诱导的信号传导途径的特异性、持续时间和幅度。
但与VEGFR 2酪氨酸磷酸化的分子基础不同,它如何转导受体信号,
膜运输和周转由各种丝氨酸/苏氨酸激酶在时空上协调,
伴侣蛋白和泛素连接酶仍然知之甚少。事实上,尽管PKC长期以来被认为是
作为VEGFR 2降解的关键介质,目前尚不清楚PKC是否直接或间接促进VEGFR 2的降解。
丝氨酸/苏氨酸磷酸化诱导的周转。在这里,我们的工作支持一个令人兴奋的新机制,
该VEGFR 2稳定性通过一种新的基于膜的信号传导复合物来调节。初步
研究中,我们发现,一种大的膜细胞骨架支架蛋白,
在神经系统和心脏中,在血管内皮细胞(EC)中表达,作为一种关键的阴性
血管生成的调节因子。新生小鼠和斑马鱼胚胎中的MIV-血影蛋白功能障碍产生衰弱
血管增生部分是由于异常高水平的VEGF/VEGFR 2信号传导,
尖端细胞数量增加。我们的数据有力地表明,HIV-血影蛋白作为一种重要的信号传导功能,
VEGFR 2通过其靶向通过直接CaMKII诱导的新的磷酸化降解的平台。
丝氨酸/苏氨酸位点。基于我们的研究结果,我们假设,在细胞内,
调节VEGFR 2磷酸化、膜运输和周转,以抑制VEGF信号传导和提示
细胞表型在萌芽血管生成。提出了两个目标来检验这一假设:1)定义ESTA IV-
血管新生萌芽过程中VEGF信号传导的血影蛋白机制; 2)建立VEGF IV-1在血管新生中的作用。
内皮尖端和柄细胞特异性血影蛋白。总的来说,这些研究的结果将解决
通过表征一种新的血管内皮生长因子IV-血影蛋白信号传导复合物,
在失败的长期VEGF相关治疗中确定新的血管靶点。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Regulation of mitochondrial fission by GIPC-mediated Drp1 retrograde transport.
- DOI:10.1091/mbc.e21-06-0286
- 发表时间:2022-01-01
- 期刊:
- 影响因子:3.3
- 作者:Ramonett A;Kwak EA;Ahmed T;Flores PC;Ortiz HR;Lee YS;Vanderah TW;Largent-Milnes T;Kashatus DF;Langlais PR;Mythreye K;Lee NY
- 通讯作者:Lee NY
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Nam Y Lee其他文献
Context-dependent activation of
上下文相关的激活
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
Y. Kim;Piyushi Gupta;Victoria M. Jones;B. Worley;Sara Shimko;D. Shin;LaTaijah C. Crawford;Chi;K. Aird;Thomas Abraham;T. Shepherd;J. Warrick;Nam Y Lee;R. Phaeton;K. Mythreye;N. Hempel;MC R130;Ph.D Mythreye Karthikeyan - 通讯作者:
Ph.D Mythreye Karthikeyan
Nam Y Lee的其他文献
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{{ truncateString('Nam Y Lee', 18)}}的其他基金
TGF-beta signaling in mitochondrial dynamics
线粒体动力学中的 TGF-β 信号传导
- 批准号:
10550422 - 财政年份:2023
- 资助金额:
$ 30.89万 - 项目类别:
Tumor-intrinsic and paracrine roles of endoglin in pancreatic cancer
内皮糖蛋白在胰腺癌中的肿瘤内在作用和旁分泌作用
- 批准号:
10742322 - 财政年份:2023
- 资助金额:
$ 30.89万 - 项目类别:
Role of spectrin signaling complex in angiogenesis
血影蛋白信号复合物在血管生成中的作用
- 批准号:
10061619 - 财政年份:2019
- 资助金额:
$ 30.89万 - 项目类别:
Mechanism of endoglin-targeted anticancer therapy
内皮糖蛋白靶向抗癌治疗机制
- 批准号:
8839215 - 财政年份:2014
- 资助金额:
$ 30.89万 - 项目类别:
Mechanism of endoglin-targeted anticancer therapy
内皮糖蛋白靶向抗癌治疗机制
- 批准号:
9245653 - 财政年份:2014
- 资助金额:
$ 30.89万 - 项目类别:
Mechanism of endoglin-targeted anticancer therapy
内皮糖蛋白靶向抗癌治疗机制
- 批准号:
9036958 - 财政年份:2014
- 资助金额:
$ 30.89万 - 项目类别:
Endoglin Regulates Endothelial Survival and Capillary Tube Stability
内皮糖蛋白调节内皮细胞存活和毛细管稳定性
- 批准号:
8111481 - 财政年份:2011
- 资助金额:
$ 30.89万 - 项目类别:
Endoglin Regulates Endothelial Survival and Capillary Tube Stability
内皮糖蛋白调节内皮细胞存活和毛细管稳定性
- 批准号:
8585870 - 财政年份:2010
- 资助金额:
$ 30.89万 - 项目类别:
Endoglin Regulates Endothelial Survival and Capillary Tube Stability
内皮糖蛋白调节内皮细胞存活和毛细管稳定性
- 批准号:
8459636 - 财政年份:2010
- 资助金额:
$ 30.89万 - 项目类别:
Endoglin Regulates Endothelial Survival and Capillary Tube Stability
内皮糖蛋白调节内皮细胞存活和毛细管稳定性
- 批准号:
8529600 - 财政年份:2010
- 资助金额:
$ 30.89万 - 项目类别:
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