Autotaxin : biochemical and functional studies

Abstract

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 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.