This thesis focuses on autotaxin (ATX), the main enzyme responsible for the production of lysophosphatidic acid (LPA). The ATX-LPA receptor axis has a wide implication in health and disease. The... Show moreThis thesis focuses on autotaxin (ATX), the main enzyme responsible for the production of lysophosphatidic acid (LPA). The ATX-LPA receptor axis has a wide implication in health and disease. The studies described in this thesis aim at characterizing the biochemical and functional properties of ATX, to advance our understanding of the molecular actions of ATX in (patho)physiology. Chapter 1 introduces LPA production and signaling, elaborates on ATX processing, activity and regulation, and highlights the role of ATX-LPA receptor signaling in development and disease. Chapter 2 reviews the latest insights of ATX and LPA receptor signaling in cancer. The prognostic value of ATX protein expression in breast cancer is explored in chapter 3. Chapter 4 describes the development and optimization of a first-generation ATX activity-based probe for in vivo screening of ATX activity. Next, the specific characteristics of the ATX_ isoform have been studied: intradomain cleavage of ATX_ and high-affinity binding to heparin are discussed in chapter 5, and the SH3 domain-mediated protein-interaction capacity of ATX_ is described in the chapter 6. In chapter 7, all results presented in this thesis are summarized and discussed. Show less
The first part of this thesis describes the development of inhibitors of autotaxin (ATX or ENPP2), a phosphodiesterase that is responsible for the production of the lipid lysophosphatidic acid (LPA... Show moreThe first part of this thesis describes the development of inhibitors of autotaxin (ATX or ENPP2), a phosphodiesterase that is responsible for the production of the lipid lysophosphatidic acid (LPA) in the circulation. ATX is implicated in several diseases including inflammation, fibrotic disease and cancer, making it an interesting potential drug target to study. ATX inhibitors are required in the validation process of ATX as a drug target. The second part of this thesis describes development of dual specificity phosphatases (DUSP) inhibitors that inhibit bacterial growth in human cells. These inhibitors act by inhibiting DUSP proteins in the host cell that are essential for bacterial growth. This approach can be used to control bacterial infection and could be a useful addition to the current treatment of bacterial infections that target solely the bacteria itself. Show less
