MECHANISMS OF HER2 HETERODIMERIZATION

HER2 异二聚化机制

基本信息

批准号：
8625276
负责人：
RON BOSE
金额：
$ 30.59万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8625276
关键词：
Antineoplastic Agents Binding Biological Assay Biological Testing Breast Breast Cancer Cell C-terminal Cancer Cell Growth Cancer cell line Cell Line Cell Proliferation Chemicals Clinical Clinical Trials Colorectal Cancer Development Dimerization Drug Targeting Drug resistance ERBB2 gene Enzyme Activation Epidermal Growth Factor Receptor ErbB4 gene Extracellular Domain Family Family member Fluorescence Resonance Energy Transfer Future Genes Growth Heterodimerization Human In Vitro Incidence Knowledge Length Lung Malignant Neoplasms Malignant neoplasm of lung Maps Mass Spectrum Analysis Measures Mediating Methods Modeling Molecular Models Monoclonal Antibodies Mutagenesis Mutation Nucleotides Oncogenes Oncogenic Patients Pertuzumab Phosphotransferases Physiological Play Process Protein Tyrosine Kinase Proteins Proto-Oncogenes Receptor Protein-Tyrosine Kinases Role Scientific Advances and Accomplishments Signal Transduction Stomach Structure System Tail Techniques Testing Trastuzumab Tyrosine Kinase Inhibitor base cancer cell cell transformation clinical practice design dimer improved in vivo knock-down lapatinib malignant breast neoplasm malignant stomach neoplasm member mimetics molecular dynamics molecular modeling monomer outcome forecast public health relevance reconstitution research study

项目摘要

DESCRIPTION (provided by applicant): Her2 is a receptor tyrosine kinase and cellular proto-oncogene that plays a major role in breast and other human cancers. Her2 is a member of the ErbB - epidermal growth factor receptor (EGFR) family. Under physiologic conditions, Her2 functions by heterodimerizing with EGFR, Her3 or Her4 and then activating its tyrosine kinase. We developed a reconstituted in vitro system to study the heterodimerization and enzyme activation of Her2. We will study the structure of Her2 heterodimers using two mass spectrometry (MS) approaches, termed chemical footprinting MS, and we will combine this with molecular dynamics simulations to obtain atom level interpretations of the MS results. Conclusions from MS and molecular dynamics will be functionally tested using Fluorescence Resonance Energy Transfer (FRET) experiments and mutagenesis experiments in cell lines. This proposal will produce a sustained, powerful influence by producing a number of scientific "firsts", chief among them is the first structural study of a Her2-Her3 heterodimer. Her2-Her3 heterodimers form a very potent signaling pair and it is has been shown that knocking down Her3 in Her2- positive breast cancer cell lines reverses oncogenic transformation. Achieving the aims of this project will advance scientific knowledge by providing new structural and functional information on Her2-Her3 and EGFR-Her2 heterodimers. Achieving the aims of this project will also advance clinical practice by identifying which Her2 and Her3 cancer associated mutations likely drive cancer cell growth and are sensitive to Her2 targeted drugs. This information will identify new patients who are likely to benefit from Her2 targeted drugs and will provide the key scientific findings to support a future breast cancer clinical trial.

描述（由申请人提供）：HER2是一种受体酪氨酸激酶和细胞原型癌，在乳腺癌和其他人类癌症中起主要作用。 HER2是ERBB-表皮生长因子受体（EGFR）家族的成员。在生理条件下，HER2通过与EGFR，HER3或HER4异二聚二聚体的功能，然后激活其酪氨酸激酶。我们开发了一个重构的体外系统，以研究HER2的异二聚化和酶激活。我们将使用两种质谱法（MS）方法（称为化学足迹MS）研究HER2异二聚体的结构，并将其与分子动力学模拟相结合，以获得MS结果的原子水平解释。 MS和分子动力学的结论将在细胞系中使用荧光共振能量转移（FRET）实验（FRET）实验和诱变实验在功能上测试。该建议将通过产生许多科学的“第一”来产生持续，强大的影响，其中首席是HER2-HER3异二聚体的首次结构研究。 HER2-HER3异二聚体形成非常有效的信号对，已经表明，在HER2-阳性乳腺癌细胞系中击倒HER3会逆转致癌转化。实现该项目的目标将通过在HER2-HER3和EGFR-HER2异二聚体上提供新的结构和功能信息来提高科学知识。实现该项目的目标还将通过确定HER2和HER3癌症相关突变可能会促进癌细胞生长并对HER2靶向药物敏感的方法来提高临床实践。这些信息将确定可能从HER2靶向药物中受益的新患者，并将提供关键的科学发现，以支持未来的乳腺癌临床试验。