Identifying endosomal Phosphatidylinositol 4-phosphate 5-kinase isoforms regulating growth factor stimulated integrin recycling and migration

鉴定调节生长因子刺激的整合素回收和迁移的内体磷脂酰肌醇 4-磷酸 5-激酶亚型

基本信息

  • 批准号:
    10217317
  • 负责人:
  • 金额:
    $ 16.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-05-01 至 2022-04-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Epithelial cells are normally non-motile but can become migratory in response to growth factor signaling. Growth factor stimulated migration plays important roles in development and is an early step in the repair process after tissue damage. During cancer progression however, growth factor signaling can become aberrantly activated through oncogenic mutation or the actions of stromal cells in the tumor microenvironment. Growth factor stimulated migration of carcinoma cells promotes metastasis and further disease progression. A thorough understanding of the signals that initiate migration in response to growth factor signaling is essential for developing interventions to either enhance migration during wound healing or inhibit adhesion and migration of cancer cells. Focal adhesions attach cells to the extracellular matrix and allow the generation of traction forces that cells use to migrate. By necessity, growth factor stimulated migration requires increased assembly of new focal adhesions, which are organized by integrins. Growth factor stimulation leads to the rapid recycling of previously internalized integrins to the plasma membrane. Previous work in the Santy lab demonstrated that cytohesin activity is required for stimulated integrin recycling and that only those cytohesin splice variants that bind phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) can initiate this trafficking process. PI(4,5)P2 is produced locally where needed from PI4P by phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks), implicating PIP5Ks in the stimulated recycling of integrins. Previous work on these understudied kinases has predominately focused on their actions at the plasma membrane during signaling and internalization of membrane proteins. The proposed studies will determine which PIP5K isoforms are required for stimulated integrin recycling and determine where within the endosomal system they produce PI(4,5)P2 to initiate stimulated integrin recycling. A knockdown and rescue strategy will be used to test the impact of PIP5K splice isoforms on integrin recycling. The location where these isoforms act will be determined by localization of both the isoforms and their product, PI(4,5)P2. In an orthogonal approach, chemically induced dimerization will be used to recruit PI(4,5)P2 producing and consuming enzymes to individual endosomal compartments to determine where local production of this lipid is required to stimulate the return of integrins to the cell surface. Understanding the steps that lead to growth factor stimulated integrin recycling will allow development of interventions to modulate this process without affecting growth factor signaling as a whole.
项目摘要 上皮细胞通常是不运动的,但可以响应于生长因子信号而变得迁移。 生长因子刺激的迁移在发育中起重要作用,是修复的早期步骤 组织损伤后的过程。然而,在癌症进展过程中,生长因子信号传导可以成为 通过致癌突变或肿瘤微环境中基质细胞的作用而异常激活。 生长因子刺激的癌细胞迁移促进转移和进一步的疾病进展。一 对响应于生长因子信号传导而启动迁移的信号的透彻理解是至关重要的 用于开发干预措施以增强伤口愈合期间的迁移或抑制粘连, 癌细胞的迁移。局灶性粘连将细胞附着在细胞外基质上, 细胞用来迁移的牵引力。出于必要,增长因素刺激的移徙需要增加 新的粘着斑的组装,其由整合素组织。生长因子刺激导致 先前内化的整联蛋白快速再循环至质膜。在Santy实验室的工作 证明了细胞粘连素活性是受刺激的整合素再循环所必需的,并且只有那些细胞粘连素 结合磷脂酰肌醇4,5-二磷酸(PI(4,5)P2)剪接变体可以启动该运输过程。 PI(4,5)P2在需要时通过磷脂酰肌醇4-磷酸5-激酶由PI 4 P局部产生 (PIP 5 Ks),暗示PIP 5 Ks参与整合素的刺激再循环。以前的工作对这些understudied 激酶主要集中在它们在信号传导期间在质膜上的作用, 膜蛋白的内化。拟议的研究将确定需要哪些PIP 5 K亚型 用于刺激整联蛋白再循环,并确定它们在内体系统内何处产生PI(4,5)P2, 启动受刺激的整合素再循环。将使用击倒和拯救策略来测试PIP 5 K的影响 剪接异构体对整合素再循环的影响。这些异构体的作用位置将通过定位来确定 这两种亚型及其产物PI(4,5)P2。在正交方法中,化学诱导的二聚 将用于将PI(4,5)P2产生和消耗酶募集到各个内体区室, 确定在哪里需要这种脂质的局部产生来刺激整合素返回细胞表面。 了解导致生长因子刺激的整合素再循环的步骤将允许开发 干预以调节这一过程,而不影响生长因子信号传导作为一个整体。

项目成果

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Lorraine C Santy其他文献

Lorraine C Santy的其他文献

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{{ truncateString('Lorraine C Santy', 18)}}的其他基金

The role of Cytohesin dependent recycling in HGF stimulated migration and tissue repair
细胞粘附素依赖性回收在 HGF 刺激迁移和组织修复中的作用
  • 批准号:
    10017071
  • 财政年份:
    2019
  • 资助金额:
    $ 16.05万
  • 项目类别:
Cytohesin dependent ARF to Rac signaling in HGF mediated motility
HGF 介导的运动中细胞粘附素依赖性 ARF 至 Rac 信号传导
  • 批准号:
    8372587
  • 财政年份:
    2012
  • 资助金额:
    $ 16.05万
  • 项目类别:
Cytohesin dependent ARF to Rac signaling in HGF mediated motility
HGF 介导的运动中细胞粘附素依赖性 ARF 至 Rac 信号传导
  • 批准号:
    8721404
  • 财政年份:
    2012
  • 资助金额:
    $ 16.05万
  • 项目类别:
Cytohesin dependent ARF to Rac signaling in HGF mediated motility
HGF 介导的运动中细胞粘附素依赖性 ARF 至 Rac 信号传导
  • 批准号:
    8547062
  • 财政年份:
    2012
  • 资助金额:
    $ 16.05万
  • 项目类别:
Cytohesin dependent ARF to Rac signaling in HGF mediated motility
HGF 介导的运动中细胞粘附素依赖性 ARF 至 Rac 信号传导
  • 批准号:
    9132250
  • 财政年份:
    2012
  • 资助金额:
    $ 16.05万
  • 项目类别:
REGULATION OF APICAL ENDOCYTOSIS BY ARF6 AND PLD
ARF6 和 PLD 对顶端内吞作用的调节
  • 批准号:
    6380353
  • 财政年份:
    2001
  • 资助金额:
    $ 16.05万
  • 项目类别:
REGULATION OF APICAL ENDOCYTOSIS BY ARF6 AND PLD
ARF6 和 PLD 对顶端内吞作用的调节
  • 批准号:
    6345559
  • 财政年份:
    2000
  • 资助金额:
    $ 16.05万
  • 项目类别:
REGULATION OF APICAL ENDOCYTOSIS BY ARF6 AND PLD
ARF6 和 PLD 对顶端内吞作用的调节
  • 批准号:
    6146803
  • 财政年份:
    1999
  • 资助金额:
    $ 16.05万
  • 项目类别:
REGULATION OF APICAL ENDOCYTOSIS BY ARF6 AND PLD
ARF6 和 PLD 对顶端内吞作用的调节
  • 批准号:
    2861398
  • 财政年份:
    1999
  • 资助金额:
    $ 16.05万
  • 项目类别:

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张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
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