Molecular Mechanism of Hepatocyte Growth Factor Signaling

肝细胞生长因子信号转导的分子机制

• 批准号: 8527071
• 负责人: Po-Han Chen
• 金额: $ 4.72万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527071
• 关键词: Address; Affinity; Antineoplastic Agents; Artificial Membranes; Basic Science; Binding; Binding Sites; Biological Assay; Cell Death; Cell physiology; Cells; Cellular Assay; Clinical Research; Colorectal Cancer; Complex; Cytoplasm; Data; Disease; Disulfides; Effectiveness; Electron Microscopy; Electrons; Embryonic Development; Engineering; Environment; Extracellular Domain; Future; Glioblastoma; Goals; Hepatocyte Growth Factor; Hepatocyte Growth Factor Receptor Signaling Pathway; Human; Immunoglobulin Domain; In Vitro; Incentives; Integral Membrane Protein; Knowledge; Lead; Length; Ligand Binding; Ligands; Light; Link; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Membrane; Methods; Microscopic; Molecular; Morphogenesis; Mutagenesis; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Process; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recombinants; Regulation; Research; Resistance; Resolution; Role; Semaphorins; Signal Transduction; Stromal Cells; Structure; Surface; System; Therapeutic; Thinking; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; X-Ray Crystallography; anticancer research; base; cancer therapy; design; extracellular; fighting; human HGF protein; in vivo; kinase inhibitor; migration; nanodisk; novel; oncology; outcome forecast; overexpression; plexin; public health relevance; receptor; receptor binding; reconstitution; therapeutic development; therapy resistant; tissue repair; tumor; tumor progression

DESCRIPTION (provided by applicant): Receptor tyrosine kinases (RTK) are evolutionarily conserved transmembrane proteins that, upon binding to extracellular ligands, initiate signaling cascades that ultimately determine a wide-spectrum of cellular functions, including differentiation, migration, survival, and cell death. Due to their fundamental roles in cellular functions, deregulation often causes diseases, such as cancer. The overall goal of the proposal is to elucidate the molecular basis of recognition/activation between hepatocyte growth factor (HGF) and its receptor MET receptor tyrosine kinase (MET RTK). In human, HGF and MET play pivotal roles in embryonic development, morphogenesis, tissue repair, and progression of malignancy. Over-expression of MET, for instance, has been found in a growing list of cancers such as lung cancer, colorectal cancer, and glioblastoma, among others. Importantly, increasing evidence suggests that HGF can confer tumor resistance to therapies, thus hampering our current anti-cancer effort. As a result, there is a major incentive to study the mechanistic basis of HGF/MET signaling in order to advance future cancer research and treatment. Using high resolution X-ray crystallography, cellular assays and other biophysical approaches (such as electron-microscopy), this proposal will aim to elucidate the molecular basis of HGF/MET recognition and activation, which will enrich our thinking of RTK signaling as well as facilitate therapeutic development against cancers. Specifically, my aims for this proposal are: 1) determination of the molecular basis of HGF-MET recognition; 2) in vivo and in vitro characterization of MET activation processes. Results from Aim 1 will reveal a novel ligand-receptor interaction mode that should aid in therapeutic development targeting the ligand-receptor interface. Results from Aim 2 will reveal how HGF binding triggers MET activation, a process that is unknown to date, and elucidation of which will direct future effort of MET inhibito design. Overall, the results from the studies should shed tremendous light on how to manipulate the system for fighting cancers.

描述（由申请人提供）：受体酪氨酸激酶（RTK）是进化上保守的跨膜蛋白，在与细胞外配体结合后，启动信号级联，最终决定广泛的细胞功能，包括分化、迁移、存活和细胞死亡。由于它们在细胞功能中的基本作用，失调通常会导致疾病，如癌症。该提案的总体目标是阐明肝细胞生长因子（HGF）及其受体MET受体酪氨酸激酶（MET RTK）之间识别/激活的分子基础。在人类中，HGF和MET在胚胎发育、形态发生、组织修复和恶性肿瘤进展中起关键作用。例如，在越来越多的癌症中发现了MET的过度表达，例如肺癌、结肠直肠癌和胶质母细胞瘤等。重要的是，越来越多的证据表明HGF可以使肿瘤对治疗产生耐药性，从而阻碍了我们目前的抗癌努力。因此，研究HGF/MET信号传导的机制基础以促进未来的癌症研究和治疗是一个主要的动机。使用高分辨率X射线晶体学，细胞分析和其他生物物理方法（如电子显微镜），该提案旨在阐明HGF/MET识别和激活的分子基础，这将丰富我们对RTK信号的思考，并促进癌症治疗的发展。具体来说，我的目的是这个建议是：1）HGF-MET识别的分子基础的测定; 2）MET激活过程的体内和体外表征。 目标1的结果将揭示一种新的配体-受体相互作用模式，有助于靶向配体-受体界面的治疗开发。目标2的结果将揭示HGF结合如何触发MET活化，这是一个迄今为止未知的过程，并且阐明这一过程将指导MET抑制剂设计的未来努力。总的来说，这些研究的结果应该为如何操纵该系统对抗癌症提供了巨大的启示。