Interactions Between p90 Ribosomal S6 Kinase and Protein Kinase A

p90 核糖体 S6 激酶和蛋白激酶 A 之间的相互作用

• 批准号: 7484242
• 负责人: TARUN B. PATEL
• 金额: $ 28.22万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7484242
• 关键词: Abbreviations; Address; Amino Acids; Apoptosis; Arsenicals; BAD gene; Bad protein; Biological; Biological Process; C-terminal; Catalytic Domain; Cell Nucleus; Cell Proliferation; Cell Proliferation Regulation; Cells; Complex; Cyan Fluorescent Protein; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclophosphamide/Fluorouracil/Prednisone; Cytoplasm; Development; Disruption; EGF gene; Enzymes; Epidermal Growth Factor; Fluorescein; Fluoresceins; Fluorescence Resonance Energy Transfer; Hand; Heart; Helix (Snails); Holoenzymes; Hypertrophy; Intervention; Localized; MATK gene; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; N-terminal; Peptides; Phosphorylation; Phosphotransferases; Play; Process; Protein Isoforms; Protein Kinase; Protein Kinase Interaction; Proteins; RPS6KA gene; Regulation; Ribosomal Protein S6 Kinase; Role; Surface Plasmon Resonance; Tuberous sclerosis protein complex; Up-Regulation; base; ear helix; inhibitor/antagonist; insight; inter-alpha-inhibitor; novel; ponasterone A; resorufin; ribosomal protein S6 kinase 1; tumor

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：p90核糖体S6激酶（RSK）是有丝分裂原活化蛋白激酶的下游效应子，在调节细胞增殖和存活中起主要作用。在这四个同工型中，RSK4是最不同的，在功能上与其他同工型也不同。 RSK1和RSK2的上调还使细胞转化和肿瘤形成。此外，在心脏中，RSK1涉及调节病理生理过程，例如肥大。该应用基于我们最近的发现，即非活动RSK1与CAMP依赖性蛋白激酶（PKA）的调节亚基（RL）相互作用，而磷酸化的活性RSK1与PKA（PKAC）的催化亚基相互作用。无活性RSK1与RL的关联降低了PKAC和RL之间的相互作用。相反，磷酸RSK1与PKAC的关联增加了PKAC和RL之间的相互作用，并降低了CAMP活跃PKA Holoenzyme的能力。此外，我们已经表明，非活性RSK1和Active RSK1与PKA亚基的相互作用允许RSK1与PKA锚定蛋白（AKAP）（AKAP）一起存在于复合体中，而PKA相互作用的破坏与AKAPS与AKAPS的破坏显着改变了细胞中活性RSK1的分布。因此，当PKA与AKAP的相互作用完整时，活动RSK1主要位于细胞核中。另一方面，当废除PKA/AKAP相互作用时，细胞核中的活性RSK1量减少，并且其细胞质中的量增加，导致胞质Rsk1底物磷酸化的磷酸化量增加。 RSK1对BAD的磷酸化增加与细胞凋亡的保护增加有关。鉴于这些发现，我们的中心假设是RSK1与PKA和AKAP的相互作用在调节PKA活性以及调节RSK1的亚细胞定位及其生物学作用方面具有功能重要意义。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，我们将追求以下特定目标。目标1：确定RSK1和PKA相互作用的亚基的区域。目标2：阐明RSK1调节PKA的机制，并确定RSK1/PKA亚基相互作用的调节。目标3：确定RSK1/PKA亚基相互作用在RSK1的细胞分布中的作用，RSK1的激活以及其生物学功能的调节。这些目标将确定PKA活性受调节的新型机制，并阐明RSK1与PKA亚基或AKAP之间在调节RSK1生物学作用中相互作用的作用。然后，这些新颖的见解可以允许开发特定的干预措施，以调节这两种激酶的某些功能。