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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 NPP-2，也称为自分泌运动因子（ATX），将溶血磷脂酰胆碱水解成胆碱和溶血磷脂酸（LPA），其是一种细胞外信号磷脂，其激活G蛋白偶联的细胞表面受体，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，如伤口愈合、脑发育和血管重塑。 ATX产生的细胞外LPA促进ras转化细胞的肿瘤侵袭、转移和新血管形成。人卵巢癌腹水中有效的促有丝分裂活性由LPA 4介导。 此外，ATX在卵巢癌中显著过表达，并且人乳腺癌的侵袭性与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，但由于缺乏关于ATX（唯一鉴定的负责产生细胞外LPA的酶）的化学和物理性质的信息，对细胞外LPA合成的基础和调节的理解受到限制。 为了了解ATX介导的LPA产生如何有助于癌症的发展和进展，并鉴定和开发LPA的小分子抑制剂，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表达的重要促转移酶的治疗化合物提供了基础。