GDE transmembrane ecto-enzymes : novel signaling functions through GPI-anchor cleavage

Abstract

Te studies described in

this thesis focus on the role of GDE2 and GDE3 on GPI-anchor

hydrolysis to increase our understanding of their physiological functions. Chapter 1 is a general introduction giving an overview of the current knowledge and progress in GPI-anchored bio-synthesis and signaling, together with an overview of the developing understanding of the mammalian GDPD protein family. Chapter 2 identifies GDE3 as the first mammalian GPI-specific PLC that selectively cleaves and releases the urokinase receptor (uPAR) from the membrane. By doing so, GDE3 negatively regulates uPAR signaling in breast cancer cells. Its closest family member, GDE2, associates with a positive clinical outcome in neuroblastoma, a childhood disease characterized by defective neuronal differentiation. The molecular mechanism involving neuronal differentiation through selective release of Glypican 6 by GDE2 is presented in Chapter 3. Addendum Chapter 3 comments on the release of GPI-anchored proteins during neuronal differentiation. Next, Chapter 4 explores the involvement of GDE2 in zebrafish development and describes a potential role for GDE2 in the development of the pancreas. Chapter 5 compares the enzymatic activity towards specifc GPI-anchored proteins and localization of GDE2 and GDE3. In Chapter 6, the results presented in this thesis are summarized and discussed.