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Glycerophosphodiesterase GDE2 Promotes Neuroblastoma Differentiation through Glypican Release and Is a Marker of Clinical Outcome

Matas-Rico, E., van Veen, M., Leyton-Puig, D., van den Berg, J., Koster, J., Kedziora, K. M., Molenaar, B., Weerts, M. J. A., de Rink, I., Medema, R. H., Giepmans, B. N. G., Perrakis, A., Jalink, K., Versteeg, R. & Moolenaar, W. H., 10-Oct-2016, In : Cancer cell. 30, 4, p. 548-562 15 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • 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
  • Rene H. Medema
  • Ben N. G. Giepmans
  • Anastassis Perrakis
  • Kees Jalink
  • Rogier Versteeg
  • Wouter H. Moolenaar

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.

Original languageEnglish
Pages (from-to)548-562
Number of pages15
JournalCancer cell
Volume30
Issue number4
Publication statusPublished - 10-Oct-2016

    Keywords

  • HIGH-RISK NEUROBLASTOMA, LYSOPHOSPHATIDIC ACID, HEPATOCELLULAR-CARCINOMA, NEURONAL DIFFERENTIATION, NEURITE RETRACTION, MEMBRANE-PROTEIN, RHO-GTPASES, PHOSPHODIESTERASE, CELLS, INHIBITION

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