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.