Non-Transcriptional Mechanisms of PEAK1 Action During TGFbeta-Induced EMT

TGFbeta 诱导的 EMT 过程中 PEAK1 作用的非转录机制

基本信息

  • 批准号:
    9208078
  • 负责人:
  • 金额:
    $ 36.25万
  • 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:
    2017-01-13 至 2020-12-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Transforming Growth Factor β (TGFβ) is a secreted protein and the first member of the TGFβ su- perfamily of ligands to be described. However, the molecular mechanisms that govern TGFβ’s ability to switch between its paradoxical growth suppressing and epithelial-mesenchymal transition (EMT) promoting functions remain to be fully elucidated. Since TGFβ elicits pleiotropic functions during normal development, adult tissue homeostasis and pathophysiological processes such as cancer and fibrosis, it is essential that future research efforts focus on producing a complete mechanistic understanding of TGFβ function. To this end, the objective of this proposal is to investigate the cellular and molecular mechanisms by which PEAK1 (pseudopodium-enriched atypical kinase one) regulates TGFβ signaling and mediates TGFβ-induced EMT during disease progression. The proposed work is an extension of our recently published and compelling preliminary data showing that (i) PEAK1 mediates TGFβ-induced EMT, migration, proliferation and cancer metastasis; (ii) PEAK1 localizes to membrane actin structures and regulates Src/Grb2/MAPK signaling in response to TGFβ/fibronectin stimulation; and (iii) inhibition of PEAK1 translation blocks the pathophysiological effects of TGFβ signaling. Thus, the central hypoth- esis of this proposal is that eIF5A-driven PEAK1 translation promotes the assembly of a Src/Grb2/PEAK1 complex in the context of membrane ITGB3 activation to enable TGFβ-induced MAPK signaling, ZEB1 upregulation and EMT. The approach is innovative because it will employ a combina- tion of state-of-the-art cellular, molecular, biochemical, microscopy, proteomic and model organism methods to elucidate the mechanisms of action for the novel eIF5A/PEAK1 translation and Src/Grb2/PEAK1/MAPK cytoskeletal signaling nodes as novel regulators of TGFβ-induced EMT. Furthermore, the proposed research is significant because it will address the following two major challenges and needs within the field of TGFβ research: Specific Aim 1 will characterize translational and post-translational mechanisms of TGFβ-induced EMT; and Specific Aim 2 will identify context- dependent spatiotemporal dynamics for molecular regulators of TGFβ responses. The collective knowledge gained from these mechanistic studies will identify and characterize details of the cellular and molecular contexts in which TGFβ is dysregulated to cause disease, and novel methods for block- ing the negative consequences of TGFβ signaling.
项目摘要 转化生长因子β(Transforming growth Factor β,TGFβ)是一种分泌性蛋白质,是TGFβ亚单位的第一个成员。 配体的每一个家族被描述。然而,控制TGFβ能力的分子机制, 在其反常生长抑制和上皮-间质转化(EMT)之间转换 促进作用有待充分阐明。由于TGFβ在正常发育过程中发挥多效性功能, 发育、成人组织稳态和病理生理过程如癌症和纤维化, 未来的研究工作必须集中在对 TGFβ功能。为此,本建议的目的是研究细胞和分子 PEAK 1(伪足富集的非典型激酶1)调节TGFβ信号传导的机制 并在疾病进展过程中介导TGFβ诱导的EMT。拟议的工作是对 我们最近发表的令人信服的初步数据表明,(i)PEAK 1介导TGFβ诱导的 EMT、迁移、增殖和癌症转移;(ii)PEAK 1定位于膜肌动蛋白结构 并响应TGFβ/纤连蛋白刺激调节Src/Grb 2/MAPK信号传导;和(iii)抑制 PEAK 1翻译的降低阻断TGFβ信号传导的病理生理学作用。因此,中央假说-- 这个提议的目的是eIF 5A驱动的PEAK 1翻译促进了一个 Src/Grb 2/PEAK 1复合物在膜ITGB 3活化的背景下使TGFβ诱导的MAPK成为可能 信号传导、ZEB 1上调和EMT。这种方法是创新的,因为它将采用一种组合- 最先进的细胞、分子、生物化学、显微镜、蛋白质组学和模式生物学 阐明新型eIF 5A/PEAK 1翻译作用机制的方法, Src/Grb 2/PEAK 1/MAPK细胞骨架信号节点作为TGFβ诱导EMT的新调节因子。 此外,拟议的研究是重要的,因为它将解决以下两个主要问题 TGFβ研究领域的挑战和需求:具体目标1将表征转化 和TGFβ诱导EMT的翻译后机制;和特异性目的2将确定背景- TGFβ反应的分子调节剂的依赖时空动力学。集体 从这些机制研究中获得的知识将识别和表征细胞的细节 和TGFβ失调导致疾病的分子背景,以及阻断TGFβ的新方法。 TGFβ信号传导的负面影响。

项目成果

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Jonathan Kelber其他文献

Jonathan Kelber的其他文献

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

California State University - Interdisciplinary Cancer Meeting (CSU-ICM)
加州州立大学 - 跨学科癌症会议 (CSU-ICM)
  • 批准号:
    10539868
  • 财政年份:
    2022
  • 资助金额:
    $ 36.25万
  • 项目类别:
Spatiotemporal mechanisms of eIF5A1/2-mediated metastasis in triple-negative breast cancer
eIF5A1/2介导的三阴性乳腺癌转移的时空机制
  • 批准号:
    10546451
  • 财政年份:
    2017
  • 资助金额:
    $ 36.25万
  • 项目类别:
Spatiotemporal mechanisms of eIF5A1/2-mediated metastasis in triple-negative breast cancer
eIF5A1/2介导的三阴性乳腺癌转移的时空机制
  • 批准号:
    10724839
  • 财政年份:
    2017
  • 资助金额:
    $ 36.25万
  • 项目类别:
Spatiotemporal mechanisms of eIF5A1/2-mediated metastasis in triple-negative breast cancer
eIF5A1/2介导的三阴性乳腺癌转移的时空机制
  • 批准号:
    10545794
  • 财政年份:
    2017
  • 资助金额:
    $ 36.25万
  • 项目类别:
Spatiotemporal mechanisms of eIF5A1/2-mediated metastasis in triple-negative breast cancer
eIF5A1/2介导的三阴性乳腺癌转移的时空机制
  • 批准号:
    10088942
  • 财政年份:
    2017
  • 资助金额:
    $ 36.25万
  • 项目类别:
Spatiotemporal mechanisms of eIF5A1/2-mediated metastasis in triple-negative breast cancer
eIF5A1/2介导的三阴性乳腺癌转移的时空机制
  • 批准号:
    10613025
  • 财政年份:
    2017
  • 资助金额:
    $ 36.25万
  • 项目类别:
Spatiotemporal mechanisms of eIF5A1/2-mediated metastasis in triple-negative breast cancer
eIF5A1/2介导的三阴性乳腺癌转移的时空机制
  • 批准号:
    10360453
  • 财政年份:
    2017
  • 资助金额:
    $ 36.25万
  • 项目类别:
SPATIOTEMPORAL MECHANISMS OF EIF5A1/2-MEDIATED METASTASIS IN TRIPLE-NEGATIVE BREAST CANCER
EIF5A1/2介导的三阴性乳腺癌转移的时空机制
  • 批准号:
    10374539
  • 财政年份:
    2017
  • 资助金额:
    $ 36.25万
  • 项目类别:

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