1. Glycerophosphodiesterase GDE2 Promotes Neuroblastoma Differentiation through Glypican Release and Is a Marker of Clinical Outcome
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Elisa Matas-Rico, Michiel van Veen, Kees Jalink, Iris de Rink, Ben N G Giepmans, Daniela Leyton-Puig, Jeroen van den Berg, Anastassis Perrakis, Rogier Versteeg, Katarzyna M. Kedziora, Jan Koster, René H. Medema, Bas Molenaar, Marjolein J.A. Weerts, Wouter H. Moolenaar, Center for Liver, Digestive and Metabolic Diseases (CLDM), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, and Oncogenomics
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0301 basic medicine ,Cancer Research ,Glypican ,NEURONAL DIFFERENTIATION ,Neurite ,Glycosylphosphatidylinositols ,INHIBITION ,Motility ,Biology ,RHO-GTPASES ,Neuroblastoma ,03 medical and health sciences ,0302 clinical medicine ,Glypicans ,NEURITE RETRACTION ,HEPATOCELLULAR-CARCINOMA ,HIGH-RISK NEUROBLASTOMA ,medicine ,Animals ,Humans ,030304 developmental biology ,0303 health sciences ,Phosphoric Diester Hydrolases ,MEMBRANE-PROTEIN ,Neurogenesis ,Cell Differentiation ,Cell Biology ,Prognosis ,medicine.disease ,Embryonic stem cell ,Cell biology ,HEK293 Cells ,030104 developmental biology ,Membrane protein ,Ectodomain ,Oncology ,030220 oncology & carcinogenesis ,CELLS ,Chickens ,LYSOPHOSPHATIDIC ACID ,PHOSPHODIESTERASE - Abstract
Neuroblastoma is a pediatric embryonal malignancy characterized by impaired neuronal differentiation. A better understanding of neuroblastoma differentiation is essential for developing new therapeutic approaches. GDE2 (encoded by GDPD5) is a six-transmembrane-domain glycerophosphodiesterase that promotes embryonic neurogenesis. We find that high GDPD5 expression is strongly associated with favorable outcome in neuroblastoma. GDE2 induces differentiation of neuroblastoma cells, suppresses cell motility, and opposes RhoA-driven neurite retraction. GDE2 alters the Rac-RhoA activity balance and the expression of multiple differentiation-associated genes. Mechanistically, GDE2 acts by cleaving (in cis) and releasing glycosylphosphatidylinositol-anchored glypican-6, a putative co-receptor. A single point mutation in the ectodomain abolishes GDE2 function. Our results reveal GDE2 as a cell-autonomous inducer of neuroblastoma differentiation with prognostic significance and potential therapeutic value.
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