Src-mediated pathways regulating adherens junction assembly.

Src 介导的途径调节粘附连接组装。

基本信息

  • 批准号:
    9310733
  • 负责人:
  • 金额:
    $ 31.38万
  • 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:
    2017-09-01 至 2022-05-31
  • 项目状态:
    已结题

项目摘要

Project Summary Endothelial barrier is regulated at the level of adherens junctions (AJs), cell-cell adhesion structures mediated by the transmembrane protein VE-cadherin. Current model suggests that the tyrosine kinase c-Src functions as a negative regulator of endothelial barrier stimulating disassembly of AJs through phosphorylation of VE cadherin. However, our studies challenge this paradigm. We found that direct activation of Src using our engineered probe transiently enhances barrier function and induces formation of morphologically distinct AJs that exhibit reduced permeability. Our preliminary evidence suggests that Src-induced enhancement of endothelial barrier is mediated through signaling pathway regulating small GTPase Arf6. We also found that phosphorylation of VE cadherin on Tyr658/Tyr731 is critical for barrier strengthening by Src. Our studies also show that Src promotes formation of new contacts with extracellular matrix (focal adhesions) and stimulates interaction of focal adhesion protein p130Cas with VE cadherin. Based on these novel findings we hypothesize that Src signaling though Arf6 and VE-cadherin, and stimulation of new focal adhesions promote formation of AJs leading to strengthening of endothelial barrier. To define the role of each pathway downstream of Src, we propose to address the following questions. 1) We will determine the role of Arf6 activity in Src-stimulated formation of AJs, and identify Src-mediated pathways that activate Arf6. 2) We will define the role of Src signaling in AJs and the role of individual phosphorylation sites on VE-cadherin in formation of new AJs and enhancement of endothelial permeability. 3) We will determine the role of focal adhesions in Src-mediated enhancement of endothelial barrier and define the role of Src signaling through specific focal adhesion proteins. The timing and location of Src-mediated signaling is critical for regulation of AJs. Thus, to achieve precise temporal and spatial control of Src-mediated processes regulating AJs, we propose to employ engineered protein tools that will allow us to regulate precisely the activity of Src and phosphorylation of VE- cadherin in living cells. The level of control is unprecedented in that Src can be selectively activated and inactivated with tight temporal control and in specific subcellular locations in living cells. Importantly, Src activation can be restricted to a specific downstream targets and subcellular locations. Using these tools, we will dissect individual Src-mediated signaling pathways controlling assembly of AJs.
项目总结

项目成果

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ANDREI V KARGINOV其他文献

ANDREI V KARGINOV的其他文献

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{{ truncateString('ANDREI V KARGINOV', 18)}}的其他基金

Optogenetic Control of Tumor Initiation and Tumor Progression in vivo
体内肿瘤发生和进展的光遗传学控制
  • 批准号:
    10640927
  • 财政年份:
    2022
  • 资助金额:
    $ 31.38万
  • 项目类别:
Regulation of endothelial cell invasion, migration and cell junction plasticity
内皮细胞侵袭、迁移和细胞连接可塑性的调节
  • 批准号:
    10406685
  • 财政年份:
    2022
  • 资助金额:
    $ 31.38万
  • 项目类别:
Optogenetic Control of Tumor Initiation and Tumor Progression in vivo
体内肿瘤发生和进展的光遗传学控制
  • 批准号:
    10413468
  • 财政年份:
    2022
  • 资助金额:
    $ 31.38万
  • 项目类别:
Regulation of endothelial cell invasion, migration and cell junction plasticity
内皮细胞侵袭、迁移和细胞连接可塑性的调节
  • 批准号:
    10685981
  • 财政年份:
    2022
  • 资助金额:
    $ 31.38万
  • 项目类别:
Synthetic Biology and Optogenetics Core
合成生物学和光遗传学核心
  • 批准号:
    10701925
  • 财政年份:
    2021
  • 资助金额:
    $ 31.38万
  • 项目类别:
Synthetic Biology and Optogenetics Core
合成生物学和光遗传学核心
  • 批准号:
    10170860
  • 财政年份:
    2021
  • 资助金额:
    $ 31.38万
  • 项目类别:
Synthetic Biology and Optogenetics Core
合成生物学和光遗传学核心
  • 批准号:
    10491052
  • 财政年份:
    2021
  • 资助金额:
    $ 31.38万
  • 项目类别:
Optogenetic tools for the dissection of oncogenic signaling mediated by kinases
用于解析激酶介导的致癌信号的光遗传学工具
  • 批准号:
    9891973
  • 财政年份:
    2018
  • 资助金额:
    $ 31.38万
  • 项目类别:
Src-mediated pathways regulating adherens junction assembly.
Src 介导的途径调节粘附连接组装。
  • 批准号:
    10166863
  • 财政年份:
    2017
  • 资助金额:
    $ 31.38万
  • 项目类别:
New methods for activation of kinases and kinase circuits in living cells.
激活活细胞中激酶和激酶电路的新方法。
  • 批准号:
    8243734
  • 财政年份:
    2012
  • 资助金额:
    $ 31.38万
  • 项目类别:

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