STRUCTURE OF THE PROMETASTATIC ENZYME AUTOTAXIN

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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.