Glycerophosphodiesterase GDE2 Promotes Neuroblastoma Differentiation through Glypican Release and Is a Marker of Clinical Outcome
Glycerophosphodiesterase GDE2 Promotes Neuroblastoma Differentiation through Glypican Release and Is a Marker of Clinical Outcome
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DOI：
10.1016/j.ccell.2016.08.016
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发表时间：
2016-10-10
期刊：
影响因子：
50.3
通讯作者：
Moolenaar, Wouter H.
中科院分区：
文献类型：
--
作者：
Matas-Rico, Elisa;van Veen, Michiel;Moolenaar, Wouter H.
神经母细胞瘤是一种以神经元分化受损为特征的儿童胚胎性恶性肿瘤。更好地了解神经母细胞瘤的分化对于开发新的治疗方法是至关重要的。GDE2(由GDPD5编码)是一种具有六个跨膜结构域的甘油磷酸二酯酶，可促进胚胎神经发生。我们发现GDPD5的高表达与神经母细胞瘤的良好预后密切相关。GDE2诱导神经母细胞瘤细胞分化，抑制细胞运动，并反对RhoA驱动的轴突回缩。GDE2改变RAC-RhoA活性平衡和多个分化相关基因的表达。在机制上，GDE2通过切割和释放糖基磷脂酰肌醇锚定的Glypcan-6来发挥作用，GDE2是一种假定的辅助受体。胞外区的单点突变会取消GDE2的功能。我们的结果表明，GDE2是神经母细胞瘤分化的细胞自主诱导剂，具有预后意义和潜在的治疗价值。
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.