Regulation of cell migration and signaling by phosphotyrosine and ubiquitin

磷酸酪氨酸和泛素对细胞迁移和信号传导的调节

基本信息

项目摘要

DESCRIPTION (provided by applicant): Cell migration is regulated by signals from cell-cell interactions, cell-matrix interactions and chemo-attractants and -repellants. Such signals are transduced and coordinated by cascades of post-translational modifications and protein-protein interactions. Specifically, Src family tyrosine kinases are activated by mitogens and adhesion receptors and phosphorylate proteins that organize the leading edge and focal adhesions in migrating cells. The Cullin 5 RING (CRL5) E3 ubiquitin ligase and SOCS proteins (phosphotyrosine-dependent substrate adaptors for CRL5) have been implicated as potential tumor suppressors. We have found that SOCS-CRL5 complexes regulate Src activity, cell migration, proliferation and/or transformation in several cell types. Inhibiting the expression of SOCS proteins or Cul5 in epithelial cells stimulates migration, proliferation, and Src kinase activity. Increased Src is necessary but not sufficient for the increased migration and proliferation of CRL5-deficient cells, suggesting that SOCS-CRL5 complexes have additional substrates. We propose three broad aims to understand in depth how CRL5 regulates Src and cell migration. First, we will determine how CRL5 regulates Src activity. Second, we will identify CRL5 substrates, focusing on those that contain phosphotyrosine, and test which substrates regulate cell migration and proliferation. Third, we will dissect the mechanisms by which SOCS proteins and substrates coordinate focal adhesion and leading edge dynamics during cell migration. Collectively, our research will show how protein-tyrosine phosphorylation and ubiquitylation cooperate to regulate cell biology.
描述(由申请人提供):细胞迁移受到来自细胞-细胞相互作用、细胞-基质相互作用以及化学引诱剂和排斥剂的信号的调节。这些信号通过翻译后修饰和蛋白质-蛋白质相互作用的级联进行转导和协调。具体来说,Src 家族酪氨酸激酶被有丝分裂原和粘附受体激活,并磷酸化组织迁移细胞中的前缘和粘着斑的蛋白质。 Cullin 5 RING (CRL5) E3 泛素连接酶和 SOCS 蛋白(CRL5 磷酸酪氨酸依赖性底物接头)被认为是潜在的肿瘤抑制因子。我们发现 SOCS-CRL5 复合物调节多种细胞类型中的 Src 活性、细胞迁移、增殖和/或转化。抑制上皮细胞中 SOCS 蛋白或 Cul5 的表达可刺激迁移、增殖和 Src 激酶活性。 Src 的增加对于 CRL5 缺陷细胞的迁移和增殖的增加是必要的,但还不够,这表明 SOCS-CRL5 复合物具有额外的底物。我们提出了三个广泛的目标来深入了解 CRL5 如何调节 Src 和细胞迁移。首先,我们将确定 CRL5 如何调节 Src 活性。其次,我们将鉴定 CRL5 底物,重点关注那些含有磷酸酪氨酸的底物,并测试哪些底物调节细胞迁移和增殖。第三,我们将剖析 SOCS 蛋白和底物在细胞迁移过程中协调粘着斑和前沿动力学的机制。总的来说,我们的研究将展示蛋白质酪氨酸磷酸化和泛素化如何协同调节细胞生物学。

项目成果

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Jonathan A Cooper其他文献

Jonathan A Cooper的其他文献

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{{ truncateString('Jonathan A Cooper', 18)}}的其他基金

Mechanisms of Purkinje cell migration
浦肯野细胞迁移机制
  • 批准号:
    8804825
  • 财政年份:
    2014
  • 资助金额:
    $ 33.7万
  • 项目类别:
Regulation of cell migration and signaling by phosphotyrosine and ubiquitin
磷酸酪氨酸和泛素对细胞迁移和信号传导的调节
  • 批准号:
    10064153
  • 财政年份:
    2014
  • 资助金额:
    $ 33.7万
  • 项目类别:
Regulation of cell migration and signaling by phosphotyrosine and ubiquitin
磷酸酪氨酸和泛素对细胞迁移和信号传导的调节
  • 批准号:
    8901233
  • 财政年份:
    2014
  • 资助金额:
    $ 33.7万
  • 项目类别:
Regulation of cell migration and signaling by phosphotyrosine and ubiquitin
磷酸酪氨酸和泛素对细胞迁移和信号传导的调节
  • 批准号:
    10295778
  • 财政年份:
    2014
  • 资助金额:
    $ 33.7万
  • 项目类别:
Regulation of cell migration and signaling by phosphotyrosine and ubiquitin
磷酸酪氨酸和泛素对细胞迁移和信号传导的调节
  • 批准号:
    10668575
  • 财政年份:
    2014
  • 资助金额:
    $ 33.7万
  • 项目类别:
Regulation of cell migration and signaling by phosphotyrosine and ubiquitin
磷酸酪氨酸和泛素对细胞迁移和信号传导的调节
  • 批准号:
    10631700
  • 财政年份:
    2014
  • 资助金额:
    $ 33.7万
  • 项目类别:
Regulation of cell migration and signaling by phosphotyrosine and ubiquitin
磷酸酪氨酸和泛素对细胞迁移和信号传导的调节
  • 批准号:
    8760249
  • 财政年份:
    2014
  • 资助金额:
    $ 33.7万
  • 项目类别:
Regulation of cell migration and signaling by phosphotyrosine and ubiquitin
磷酸酪氨酸和泛素对细胞迁移和信号传导的调节
  • 批准号:
    9067447
  • 财政年份:
    2014
  • 资助金额:
    $ 33.7万
  • 项目类别:
Receptor Tyrosine Kinases: Biology and Cancer
受体酪氨酸激酶:生物学和癌症
  • 批准号:
    7916135
  • 财政年份:
    2010
  • 资助金额:
    $ 33.7万
  • 项目类别:
Normal and Cancer Stem Cells of the Mammary Gland
乳腺的正常干细胞和癌症干细胞
  • 批准号:
    8300983
  • 财政年份:
    2009
  • 资助金额:
    $ 33.7万
  • 项目类别:
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