Glycerophosphodiesterase GDE2 Promotes Neuroblastoma Differentiation through Glypican Release and Is a Marker of Clinical Outcome.
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.
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Elisa
E
Matas-Rico
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Michiel
M
van Veen
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Daniela
D
Leyton-Puig
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Jeroen
J
van den Berg
Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
Jan
J
Koster
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Katarzyna M
KM
Kedziora
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Bas
B
Molenaar
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Marjolein J A
MJ
Weerts
Deep Sequencing Core Facility, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
Iris
I
de Rink
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
René H
RH
Medema
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Ben N G
BN
Giepmans
Division of Biochemistry, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
Anastassis
A
Perrakis
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Kees
K
Jalink
Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
Rogier
R
Versteeg
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: w.moolenaar@nki.nl.
Wouter H
WH
Moolenaar
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002645:Chickens; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D053673:Glypicans / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011379:Prognosis
C120300:GPC6 protein, human; D017261:Glycosylphosphatidylinositols; D053673:Glypicans; D010727:Phosphoric Diester Hydrolases; C038133:glycerophosphodiester phosphodiesterase