STRUCTURE OF THE PROMETASTATIC ENZYME AUTOTAXIN

促转移酶自分泌因子的结构

• 批准号: 8169317
• 负责人: DEMETRIOS BRADDOCK
• 金额: $ 0.7万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169317
• 关键词: Brain; Cell Proliferation; Cell Surface Receptors; Chemicals; Choline; Computer Retrieval of Information on Scientific Projects Database; Development; Enzymes; Event; Foundations; Funding; GTP-Binding Proteins; Generations; Grant; Human; Hydrolysis; Institution; Lead; Lysophospholipids; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Neoplasm Metastasis; Organism; Ovarian Carcinoma; Peritoneal Fluid; Phospholipids; Play; Production; Regulation; Research; Research Personnel; Resources; Role; Signal Transduction; Source; Structure; Tumor Cell Invasion; United States National Institutes of Health; Vascular remodeling; Wound Healing; base; cell transformation; extracellular; inhibitor/antagonist; lysophosphatidic acid; malignant breast neoplasm; migration; neovascularization; overexpression; physical property; small molecule; therapeutic development; three dimensional structure; tumorigenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. NPP-2, also known as Autotaxin (ATX) hydrolyzes lysophosphatidyl choline into choline and lysophosphatidic acid (LPA), an extracellular signaling phospholipid that activates G-protein-coupled cell surface receptors, triggers cell proliferation, migration, and survival, and ultimately mediates events central to organism fate such as wound healing, brain development and vascular remodeling. Generation of extracellular LPA by ATX promotes tumor invasion, metastasis, and neovascularization of ras-transformed cells. The potent mitogenic activity in human ovarian cancer ascitic fluid is mediated by LPA4. In addition, ATX is markedly overexpressed in ovarian carcinoma, and the invasiveness of human breast cancer correlates directly with ATX expression. Despite the important roles LPA and ATX play in cell signaling, development and oncogenesis, understanding the basis and regulation of extracellular LPA synthesis has been limited by a lack of information regarding the chemical and physical properties of ATX, the only identified enzyme responsible for generating extracellular LPA. To understand how ATX-mediated LPA production contributes to cancer development and progression, and to identify and develop small molecule inhibitors of LPA, we determined the three dimensional structure of the human enzyme and identified lead small molecule inhibitors. These studies provide the foundation for the rational development of therapeutic compounds directed against an important pro-metastatic enzyme overexpressed in a variety of highly malignant tumors.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 NPP-2，也称为自分泌运动因子 (ATX)，可将溶血磷脂酰胆碱水解成胆碱和溶血磷脂酸 (LPA)，溶血磷脂酸是一种细胞外信号磷脂，可激活 G 蛋白偶联细胞表面受体，触发细胞增殖、迁移和存活，并最终介导对生物体命运至关重要的事件，例如伤口愈合、大脑发育和血管生成 重塑。 ATX 产生细胞外 LPA 促进肿瘤侵袭、转移和 ras 转化细胞的新血管形成。人卵巢癌腹水中的有效促有丝分裂活性由 LPA4 介导。 此外，ATX在卵巢癌中显着过表达，人类乳腺癌的侵袭性与ATX表达直接相关。 尽管 LPA 和 ATX 在细胞信号传导、发育和肿瘤发生中发挥重要作用，但由于缺乏有关 ATX 化学和物理特性的信息，对细胞外 LPA 合成的基础和调节的了解受到限制，ATX 是唯一已确定的负责生成细胞外 LPA 的酶。 为了了解 ATX 介导的 LPA 产生如何促进癌症的发生和进展，并鉴定和开发 LPA 小分子抑制剂，我们确定了人类酶的三维结构并鉴定了先导小分子抑制剂。这些研究为合理开发针对多种高度恶性肿瘤中过度表达的重要促转移酶的治疗化合物奠定了基础。