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P90核糖体S6激酶(RSK)是丝裂原激活蛋白的直接下游效应因子 在细胞增殖和存活的调节中起着重要作用。在四种异构体中,RSK4 是与其他异构体最不同的,也是功能上最不同的。RSK1和RSK1基因的上调 RSK2也使细胞易于转化和肿瘤形成。此外,在心脏中,RSK1参与了 调节肥大等病理生理过程。此应用程序基于我们最新的 失活的RSK1与cAMP依赖的蛋白激酶调节亚单位(RL)相互作用的研究结果 (PKA),而磷酸化的活性RSK1与PKA的催化亚单位(PKAc)相互作用。这个 失活的RSK1与RL的结合减少了PKAc和RL之间的相互作用。相比之下, 磷酸化RSK1与PKAc的结合增加了PKAc和RL之间的相互作用,并降低了 CAMP激活PKA全酶的能力。此外,我们已经证明了不活跃的相互作用 具有PKA亚基的RSK1和活性RSK1允许RSK1存在于具有PKA锚定的复合体中 蛋白(AKAP)以及PKA与AKAP相互作用的中断显著改变了AKAP的分布 细胞内的活性RSK1。因此,当PKA与AKAP的相互作用完整时,活性RSK1被定位 主要是在细胞核中。另一方面,当PKA/AKAP互动被取消时, 核内活性RSK1的数量减少,细胞质中的活性RSK1数量增加 胞浆RSK1底物结节性硬化症复合体2(TSC2)的磷酸化增加 而且很糟糕。RSK1对BAD的磷酸化增加与增强对BAD的保护有关 细胞凋亡。鉴于这些发现,我们的中心假设是RSK1与PKA的相互作用 而AKAP在调节PKA活性和调节细胞外信号转导通路中具有重要的功能意义 RSK1的亚细胞定位及其生物学作用。为了解决这一假设并确定 调节RSK1和PKA亚基之间相互作用的机制,我们将进行以下研究 明确的目标。目的1:确定RSK1上与PKA亚基相互作用的区域。 目的2:阐明RSK1对PKA的调控机制并确定其调控机制 RSK1/PKA亚基相互作用的研究。目的3:确定RSK1/PKA亚单位相互作用在细胞周期中的作用。 RSK1的细胞分布,RSK1的激活及其生物学功能的调节。这些目标将 确定调控PKA活性的新机制,并阐明PKA的作用 RSK1与PKA亚基或AKAP的相互作用在调节RSK1的生物学作用中的作用。这些 然后,新的见解可能会允许开发特定的干预措施,以规范某些功能 这两种蛋白都是。
英文摘要
The p90 Ribosomal S6 kinases (RSKs) are immediately downstream effectors of mitogen activated protein kinases and play a major role in regulation of cell proliferation and survival. Among the four isoforms, RSK4 is the most dissimilar and also functionally different from the other isoforms. The upregulation of RSK1 and RSK2 also predisposes cells to transformation and tumor formation. Moreover, in the heart, RSK1 is involved regulating pathophysiological processes such as hypertrophy. This application is based on our recent findings that inactive RSK1 interacts with the regulatory subunit (Rl)of cAMP dependent protein kinase (PKA) while the phosphorylated, active RSK1 interacts with the catalytic subunit of PKA (PKAc). The association of inactive RSK1 with Rl decreases interactions between PKAc and Rl. In contrast, the association of phospho- RSK1 with PKAc increases interactions between PKAc and Rl and decreases the ability of cAMP to active the PKA holoenzyme. Additionally, we have shown that the interactions of inactive RSK1 and active RSK1 with subunits of PKA permits the RSK1 to exist in a complex with PKA anchoring proteins (AKAPs) and the disruption of PKA interactions with AKAPs dramatically alters the distribution of active RSK1 in cells. Thus, when interactions of PKA with AKAPs are intact, the active RSK1 is localized primarily in the nucleus of cells. On the other hand, when the PKA/AKAP interactions are abolished, the amount of active RSK1 in the nucleus is decreased and its amount in the cytoplasm is increased with a resultant increase in phosphorylation of the cytosolic RSK1 substrates tuberous sclerosis complex 2 (TSC2) and BAD. Increased phosphorylation of BAD by RSK1 is associated with an increase in protection from cellular apoptosis. Given these findings, our central hypothesis is that the interactions of RSK1 with PKA and AKAPs are of functional significance in regulating the activity of PKA as well as modulating the subcellular localization of RSK1 and its biological actions. To address this hypothesis and to identify the mechanisms that regulate interactions between RSK1 and PKA subunits, we will pursue the following specific aims. Aim 1: To identify the regions on RSK1 and the subunits of PKA that interact with each other. Aim 2: To elucidate the mechanisms involved in regulation of PKA by RSK1 and to determine the regulation of RSK1/PKA subunit interactions. Aim 3: To determine the role of RSK1/PKA subunit interactions in the cellular distribution of RSK1, the activation of RSK1, and regulation of its biological functions. These aims will identify novel mechanisms by which PKA activity is regulated and also elucidate of the role of the interactions between RSK1 with PKA subunits or AKAPs in regulating the biological actions of RSK1. These novel insights may then permit the development of specific interventions that regulate certain functions of both these kinases.
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Role of Sprouty 2 in Hepatocellular Carcinoma
  • 批准号:
    8634299
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2014
  • 负责人:
    TARUN B. PATEL
  • 依托单位:
Role of Sprouty 2 in Hepatocellular Carcinoma
  • 批准号:
    8810587
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2014
  • 负责人:
    TARUN B. PATEL
  • 依托单位:
Interactions Between p90 Ribosomal S6 Kinase and Protein Kinase A
  • 批准号:
    7917102
  • 项目类别:
  • 资助金额:
    $21.74万
  • 财政年份:
    2009
  • 负责人:
    TARUN B. PATEL
  • 依托单位:
Interactions Between p90 Ribosomal S6 Kinase and Protein Kinase A
  • 批准号:
    7894448
  • 项目类别:
  • 资助金额:
    $27.93万
  • 财政年份:
    2007
  • 负责人:
    TARUN B. PATEL
  • 依托单位:
海外基金