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Glycerophosphodiesterase GDE2 Promotes Neuroblastoma Differentiation through Glypican Release and Is a Marker of Clinical Outcome Matas-Rico, Elisa van Veen, Wouter H Leyton-Puig, Daniela van den Berg, Jeroen Koster, Jan Kedziora, Katarzyna M Molenaar, Bas J A Weerts, Marjolein de Rink, Iris Medema, René H Giepmans, Ben N G Perrakis, Anastassis Jalink, Kees Versteeg, Rogier van Veen Neuroblastoma 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. 2024-10-07T09:59:50Z 2024-10-07T09:59:50Z 2016-10 journal article Elisa Matas-Rico, Michiel van Veen, Daniela Leyton-Puig, Jeroen van den Berg, Jan Koster, Katarzyna M. Kedziora, Bas Molenaar, Marjolein J.A. Weerts, Iris de Rink, René H. Medema, Ben N.G. Giepmans, Anastassis Perrakis, Kees Jalink, Rogier Versteeg, Wouter H. Moolenaar, Glycerophosphodiesterase GDE2 Promotes Neuroblastoma Differentiation through Glypican Release and Is a Marker of Clinical Outcome, Cancer Cell, Volume 30, Issue 4, 2016, Pages 548-562, ISSN 1535-6108, https://doi.org/10.1016/j.ccell.2016.08.016. https://hdl.handle.net/10630/34419 10.1016/j.ccell.2016.08.016 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier