Dynamics and Topology of Phosphotyrosine-SH2 Interaction Networks

磷酸酪氨酸-SH2相互作用网络的动力学和拓扑

基本信息

批准号：
8294600
负责人：
BRUCE J. MAYER
金额：
$ 49.47万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8294600
关键词：
Address Behavior Binding Binding Proteins Binding Sites Biochemical Biological Biological Assay Biological Models Cell Extracts Cell Surface Receptors Cells Co-Immunoprecipitations Color Complex Computer Simulation Coupled Coupling Databases Development Dissociation EGF gene Environment Epidermal Growth Factor Receptor Epithelial Cells Equation Event Fibroblasts Goals Heregulin Human Image In Situ Individual Instruction Knowledge Life Ligation Link Malignant Neoplasms Maps Mass Spectrum Analysis Medicine Mesenchymal Methods Modeling Molecular Monitor Mutation Neuronal Differentiation Oncogenic Outcome Output PC12 Cells PDGFRB gene PTB Domain Pathway interactions Patients Pharmaceutical Preparations Phosphopeptides Phosphotyrosine Play Process Protein Tyrosine Kinase Proteins Receptor Cell Receptor Protein-Tyrosine Kinases Receptor Signaling Recruitment Activity Role Signal Transduction Site System Technology Therapeutic Intervention Time Tyrosine Tyrosine Phosphorylation Validation base cancer therapy cell motility cell type data integration design human disease imaging modality in vivo information processing innovation insight receptor response single molecule src Homology Region 2 Domain transmission process

项目摘要

DESCRIPTION (provided by applicant): Cell surface receptors linked to tyrosine kinases control a host of important cellular activities, including proliferation, differentiation, and motility. Disregulated tyrosine kinase signaling is a common feature of many human cancers, thus tyrosine kinases and their downstream effectors are targets for the development of new drugs for the treatment of cancer. In order to take full advantage of such promising new therapies, however, we need an understanding of how tyrosine kinase signaling networks process information on a systems level. While considerable progress has been made in developing quantitative models describing tyrosine kinase signaling networks, these efforts are severely hampered by a lack of quantitative information on how changes in tyrosine phosphorylation are coupled to their downstream effectors containing modular phosphotyrosine binding domains. The goals of this collaborative project are to take advantage of new experimental approaches to address this gap in knowledge directly. Specifically, we will use SH2 profiling, a phosphoproteomic approach that is highly complementary to mass spectrometry-based methods, to quantify dynamic changes in binding sites for specific effector proteins upon receptor tyrosine kinase activation. Responses to different receptors and in different cell types will be compared, allowing systems-level behavior to be correlated with biological outputs. We will also use single-molecule imaging methods to monitor the coupling of specific effectors to receptors in the intracellular environment. These studies will afford unprecedented insight into the interaction dynamics of receptor signaling complexes that will enable much more powerful and accurate models of tyrosine kinase signaling. RELEVANCE (See instructions): Signaling from receptors with tyrosine kinase activity plays an important role in a number of human diseases, in particular cancer. Quantitative computer-based models that accurately describe the signaling mechanism used by these receptors will be very useful in designing new therapies for cancer and in deciding which patients will benefit most from those therapies (individualized medicine). The proposed studies use innovative experimental approaches to reveal new mechanistic insights necessary for building more powerful and accurate models.

描述（由申请人提供）：与酪氨酸激酶有关的细胞表面受体控制着许多重要的细胞活性，包括增殖，分化和运动。无调酪氨酸激酶信号传导是许多人类癌症的共同特征，因此酪氨酸激酶及其下游效应子是开发新药物治疗癌症的靶标。但是，为了充分利用这种有希望的新疗法，我们需要了解酪氨酸激酶信号网络如何在系统级别上处理信息。尽管在开发描述酪氨酸激酶信号网络的定量模型方面取得了很大进展，但由于缺乏有关如何将酪氨酸磷酸化的变化耦合到其下游效应器中，这些努力严重阻碍了这些努力。这个协作项目的目标是利用新的实验方法直接解决这一差距。具体而言，我们将使用SH2 PROPILING，这是一种与基于质谱的方法相互互补的磷酸蛋白质组学方法，以量化受体酪氨酸激酶激活的特定效应蛋白的结合位点的动态变化。将比较对不同受体和不同细胞类型中的反应，从而使系统级别的行为与生物输出相关。我们还将使用单分子成像方法来监测特定效应子与受体在细胞内环境中的耦合。这些研究将提供对受体信号传导复合物相互作用动力学的前所未有的见解，这将使酪氨酸激酶信号的更强大和准确的模型。相关性（请参阅说明）：酪氨酸激酶活性受体的信号传导在许多人类疾病，尤其是癌症中起着重要作用。准确描述这些受体使用的信号传导机制的基于计算机的定量模型将在设计新的癌症疗法以及决定哪些患者中受益最大的疗法（个性化医学）非常有用。拟议的研究使用创新的实验方法来揭示建立更强大和准确的模型所需的新机械见解。