Non-Smad Mechanisms of TGFBeta Signaling

TGFBeta 信号转导的非 Smad 机制

基本信息

  • 批准号:
    7827981
  • 负责人:
  • 金额:
    $ 31.66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-04-01 至 2010-03-31
  • 项目状态:
    已结题

项目摘要

Development and tissue differentiation isdictated by secreted growth and differentiation factors. Among these, members of the TGF-beta superfamily are well known to play key roles. TGF-beta and related proteins also play key roles in normal lung development, while TGF-beta itself plays an important role in the response to injury. TGF-beta expression and signaling also contributes to pathobiology of some lung diseases and to carcinoma development and progression. Consequently the mechanisms of TGF-beta signaling have been of great interest in both normal development and in pathology. TGF-beta and related proteins signal through heteromeric, cell surface complexes of two types of transmembrane serine-threonine kinase receptors, which in turn activate, through phosphorylation, the Smads. Smad proteins act as intracellular effectors of TGF-beta signals that, following activation and heteromerization, translocate into the nucleus where they elaborate the ligand-induced transcription responses of many genes. The TGF-beta-induced Smad signaling pathway is now well accepted and its model of activation and mechanism of action are well developed. Increasing evidence, however, points out that the TGF-beta activation of the receptor complex also initiates other, non-Smad signaling pathways. Some of these observations are now being recognize, but very little is known about these non-Smad signaling mechanisms, how they link to receptors and what role they play inthe TGF-beta induced cellular response. Some of these parallel pathways may directlyregulate Smad signaling,while others may effect unrelated responses. This research proposal works from the hypothesis that these TGF-beta-induced non-Smad signaling pathways greatly contributeto the cellular response to TGF-beta and related factors. We propose to initiatea research program aimed at defining several TGF-beta-induced non-Smad signaling pathways, thereby specifically focusing on the activation of Erk MAP kinase, p38 MAP kinase, JNK and RhoA signaling in response to TGF-beta. The four Aims of this proposal will study how the activtion of these pathways is biochemically and mechanistically linked to the activation of the TGF-beta receptors and how they affect the cellular response to TGF-beta at the level of Smad activation and gene expression. Together, these studies should provide insight into the mechanisms of action of TGF-beta and related factors in normal development and inpathobiology.
发育和组织分化由分泌的生长和分化因子决定。其中, 众所周知,TGF-β超家族的成员起关键作用。TGF-β和相关蛋白质也发挥作用, TGF-β在正常肺发育中起关键作用,而TGF-β本身在对损伤的反应中起重要作用。 TGF-β的表达和信号传导也有助于某些肺部疾病和癌症的病理生物学 发展和进步。因此,TGF-β信号传导的机制已经引起了人们的极大兴趣, 无论是正常发育还是病理学。TGF-β和相关蛋白通过异聚体细胞表面信号传导 两种类型的跨膜丝氨酸-苏氨酸激酶受体的复合物,其依次通过 磷酸化,Smads。Smad蛋白作为TGF-β信号的细胞内效应物, 激活和异聚化,易位到细胞核中,在那里它们阐述配体诱导的转录 许多基因的反应。TGF-β诱导的Smad信号通路现在已被广泛接受,其模型 激活和作用机制已得到充分发展。然而,越来越多的证据指出,TGF-β 受体复合物的激活也启动其它非Smad信号通路。其中一些意见 现在已经被认识到,但对这些非Smad信号传导机制知之甚少,它们如何与 受体及其在TGF-β诱导的细胞反应中的作用。其中一些平行途径可能 直接调节Smad信号,而其他可能影响无关的反应。这项研究计划从 假设这些TGF-β诱导的非Smad信号通路极大地促进了细胞内 对TGF-β及相关因素的反应。我们提议启动一项研究计划, TGF-β诱导的非Smad信号通路,从而特异性地集中于Erk MAP激酶的激活, p38 MAP激酶、JNK和RhoA信号转导对TGF-β的响应。本提案的四个目标将研究如何 这些通路的激活在生物化学和机械上与TGF-β的激活相关, 受体以及它们如何在Smad激活和基因水平上影响细胞对TGF-β的反应 表情总之,这些研究应该提供深入了解TGF-β和相关的作用机制, 正常发育和非病理生物学因素。

项目成果

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RIK M DERYNCK其他文献

RIK M DERYNCK的其他文献

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{{ truncateString('RIK M DERYNCK', 18)}}的其他基金

Central role of ShcA in differential TGF-beta signaling, epithelial plasticity and carcinoma cell behavior
ShcA 在差异 TGF-β 信号传导、上皮可塑性和癌细胞行为中的核心作用
  • 批准号:
    9105649
  • 财政年份:
    2016
  • 资助金额:
    $ 31.66万
  • 项目类别:
Central role of ShcA in differential TGF-beta signaling, epithelial plasticity and carcinoma cell behavior
ShcA 在差异 TGF-β 信号传导、上皮可塑性和癌细胞行为中的核心作用
  • 批准号:
    9894637
  • 财政年份:
    2016
  • 资助金额:
    $ 31.66万
  • 项目类别:
Central role of ShcA in differential TGF-beta signaling, epithelial plasticity and carcinoma cell behavior
ShcA 在差异 TGF-β 信号传导、上皮可塑性和癌细胞行为中的核心作用
  • 批准号:
    9237246
  • 财政年份:
    2016
  • 资助金额:
    $ 31.66万
  • 项目类别:
Central role of ShcA in differential TGF-beta signaling, epithelial plasticity and carcinoma cell behavior
ShcA 在差异 TGF-β 信号传导、上皮可塑性和癌细胞行为中的核心作用
  • 批准号:
    9452037
  • 财政年份:
    2016
  • 资助金额:
    $ 31.66万
  • 项目类别:
PRMT1 MEDIATED ARG METHYLATION OF INHIBITORY SMADS IN TGF-BETA SIGNALLING
PRMT1 介导 TGF-β 信号传导中抑制性 SMAD 的 ARG 甲基化
  • 批准号:
    8363822
  • 财政年份:
    2011
  • 资助金额:
    $ 31.66万
  • 项目类别:
PRMT1 MEDIATED ARG METHYLATION OF INHIBITORY SMADS IN TGF-BETA SIGNALLING
PRMT1 介导 TGF-β 信号传导中抑制性 SMAD 的 ARG 甲基化
  • 批准号:
    8169818
  • 财政年份:
    2010
  • 资助金额:
    $ 31.66万
  • 项目类别:
Regulatory non-Smad signaling in TGF-b-induced epithelial-mesenchymal transition
TGF-b 诱导的上皮间质转化中的调节性非 Smad 信号传导
  • 批准号:
    9197271
  • 财政年份:
    2009
  • 资助金额:
    $ 31.66万
  • 项目类别:
TGF-beta-induced non-Smad signaling events and cancer cell behavior
TGF-β诱导的非Smad信号传导事件和癌细胞行为
  • 批准号:
    7565384
  • 财政年份:
    2009
  • 资助金额:
    $ 31.66万
  • 项目类别:
TGF-b family signaling in cardiomyocyte differentiation from embryonic stem cells
胚胎干细胞向心肌细胞分化中的 TGF-b 家族信号传导
  • 批准号:
    7738990
  • 财政年份:
    2009
  • 资助金额:
    $ 31.66万
  • 项目类别:
Regulatory non-Smad signaling in TGF-b-induced epithelial-mesenchymal transition
TGF-b 诱导的上皮间质转化中的调节性非 Smad 信号传导
  • 批准号:
    8632683
  • 财政年份:
    2009
  • 资助金额:
    $ 31.66万
  • 项目类别:

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