STRUCTURE OF THE PROMETASTATIC ENZYME AUTOTAXIN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 NPP-2，也被称为自体趋化蛋白(ATX)，将溶血磷脂酰胆碱水解为胆碱和溶血磷脂酸(LPA)，LPA是一种细胞外信号磷脂，激活G蛋白偶联的细胞表面受体，触发细胞增殖、迁移和生存，最终介导创伤愈合、脑发育和血管重塑等生物体命运的核心事件。ATX产生的胞外LPA促进肿瘤的侵袭、转移和ras转化细胞的新生血管形成。人卵巢癌腹水中强大的促有丝分裂活性是由LPA4介导的。此外，ATX在卵巢癌中明显过表达，人类乳腺癌的侵袭性与ATX的表达直接相关。 尽管LPA和ATX在细胞信号转导、发育和肿瘤发生中发挥着重要作用，但由于缺乏有关ATX的化学和物理性质的信息，对胞外LPA合成的基础和调控的了解一直受到限制。ATX是唯一被发现的负责产生胞外LPA的酶。为了了解ATX介导的LPA产生如何促进癌症的发生和发展，以及识别和开发LPA的小分子抑制剂，我们测定了人酶的三维结构，并确定了铅小分子抑制剂。这些研究为针对一种在多种高度恶性肿瘤中过度表达的重要转移酶的治疗化合物的合理开发提供了基础。

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.