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

Matas-Rico, Elisa; Veen, Michiel van; Leyton-Puig, Daniela; Berg, Jeroen van den; Koster, Jan; Kedziora, Katarzyna M.; Molenaar, Bas; Weerts, Marjolein J.A.; Rink, Iris de; Medema, René H.; Giepmans, Ben N. G.; Perrakis, Anastassis; Jalink, Kees; Versteeg, Rogier

doi:10.1016/j.ccell.2016.08.016

Cited by 54 publications

(95 citation statements)

References 57 publications

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“…This implies that GDE2 enzymatic regulation of specific GPI-anchored proteins is central to its function in neuronal survival. We conducted a proteomic screen to identify GPI-anchored substrates of GDE2 and found Glypican 4 and 6, both of which have been reported as GDE2 substrates [9, 13]. We then demonstrated that the non-membrane versions of these proteins, as well as Glypican 1, are reduced in SOD1 G93A mice.…”

Section: Discussionmentioning

confidence: 94%

“…Protein complexes that yielded more signal in the WT, indicative of impaired GPI-anchor cleavage in the Gde2 KO, were then identified using mass spectrometry. This screen identified two members of the Glypican family of heparin sulfate proteoglycans, Glypican 6 and Glypican 4, and both of these GPI-anchored proteins have been reported as substrates of GDE2 [9, 13]. We hypothesized that if the production of non-membrane bound Glypican 4 and Glypican 6 via GPI-anchor cleavage was crucial to prevent degeneration, we should see diminished production of these proteins in mouse models that exhibit motor neuron degeneration.…”

Section: Resultsmentioning

confidence: 99%

“…This leads to a non-cell autonomous decrease in Notch signaling in neighboring progenitors, promoting cell-cycle exit and differentiation. Similarly, GDE2 mediated cleavage of Glypican 6 at the cell surface has recently been reported to promote the differentiation of neuroblastoma cells [13]. GPI-anchor cleaving activities were also detected in GDE3 and GDE6, providing evidence that the six-transmembrane GDEs are the first known GPI-anchor cleaving enzymes in mammals that function at the cell surface [9].…”

Section: Introductionmentioning

confidence: 99%

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GDE2 is essential for neuronal survival in the postnatal mammalian spinal cord

Cave¹,

Park²,

Rodriguez³

et al. 2017

Mol Neurodegeneration

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BackgroundGlycerophosphodiester phosphodiesterase 2 (GDE2) is a six-transmembrane protein that cleaves glycosylphosphatidylinositol (GPI) anchors to regulate GPI-anchored protein activity at the cell surface. In the developing spinal cord, GDE2 utilizes its enzymatic function to regulate the production of specific classes of motor neurons and interneurons; however, GDE2’s roles beyond embryonic neurogenesis have yet to be defined.MethodUsing a panel of histological, immunohistochemical, electrophysiological, behavioral, and biochemistry techniques, we characterized the postnatal Gde2 −/− mouse for evidence of degenerative neuropathology. A conditional deletion of Gde2 was used to study the temporal requirements for GDE2 in neuronal survival. Biochemical approaches identified deficits in the processing of GPI-anchored GDE2 substrates in the SOD1 G93A mouse model of familial Amyotrophic Lateral Sclerosis that shows robust motor neuron degeneration.ResultsHere we show that GDE2 expression continues postnatally, and adult mice lacking GDE2 exhibit a slow, progressive neuronal degeneration with pathologies similar to human neurodegenerative disease. Early phenotypes include vacuolization, microgliosis, cytoskeletal accumulation, and lipofuscin deposition followed by astrogliosis and cell death. Remaining motor neurons exhibit peripheral motor unit restructuring causing behavioral motor deficits. Genetic ablation of GDE2 after embryonic neurogenesis is complete still elicits degenerative pathology, signifying that GDE2’s requirement for neuronal survival is distinct from its involvement in neuronal differentiation. Unbiased screens identify impaired processing of Glypican 4 and 6 in Gde2 null animals, and Glypican release is markedly reduced in SOD1 G93A mice.ConclusionsThis study identifies a novel function for GDE2 in neuronal survival and implicates deregulated GPI-anchored protein activity in pathways mediating neurodegeneration. These findings provide new molecular insight for neuropathologies found in multiple disease settings, and raise the possibility of GDE2 hypofunctionality as a component of neurodegenerative disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0148-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

GDE2 is essential for neuronal survival in the postnatal mammalian spinal cord

Cave¹,

Park²,

Rodriguez³

et al. 2017

Mol Neurodegeneration

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“…We specifically used the following datasets: Neuroblastoma Ghent (Array Express: E-MTAB-2618) [19] and Neuroblastoma SEQC (GEO: GSE62564). Kaplan Mier curves were obtained through R2 as described by Matas-Rico E et al [35]. …”

Section: Methodsmentioning

confidence: 99%

Altered expression of miRNAs and methylation of their promoters are correlated in neuroblastoma

Maugeri

Barbagallo

et al. 2016

Oncotarget

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Neuroblastoma is the most common human extracranial solid tumor during infancy. Involvement of several miRNAs in its pathogenesis has been ascertained. Interestingly, most of their encoding genes reside in hypermethylated genomic regions: thus, their tumor suppressor function is normally disallowed in these tumors. To date, the therapeutic role of the demethylating agent 5′-Aza-2 deoxycytidine (5'-AZA) and its effects on miRNAome modulation in neuroblastoma have not been satisfactorily explored. Starting from a high-throughput expression profiling of 754 miRNAs and based on a proper selection, we focused on miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p as candidate miRNAs for our analysis. They resulted downregulated in four neuroblastoma cell lines with respect to normal adrenal gland. MiRNAs 29a-3p and 34b-3p also resulted downregulated in vivo in a murine neuroblastoma progression model. Unlike the amount of methylation of their encoding gene promoters, all these miRNAs were significantly overexpressed following treatment with 5′-AZA. Transfection with candidate miRNAs mimics significantly decreased neuroblastoma cells proliferation rate. A lower expression of miR-181c was significantly associated to a worse overall survival in a public dataset of 498 neuroblastoma samples (http://r2.amc.nl). Our data strongly suggest that CDK6, DNMT3A, DNMT3B are targets of miR-29a-3p, while CCNE2 and E2F3 are targets of miR-34b-3p. Based on all these data, we propose that miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p are disallowed tumor suppressor genes in neuroblastoma and suggest them as new therapeutic targets in neuroblastoma.

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“…Similarly, another study has shown that neuroblastoma differentiation is promoted by release of a GPI-anchored HSPG, Glypican-6 (GPC6) through via Glycerophosphodiesterase (GDE2). This study also found that high GDE2 or low GPC6 level in neuroblastoma predicted significantly increased patient survival (108). These studies are of high significance as they make two major points; first, that the differentiation state of the cancer cells predict survival, and second, that HS and HSPGs are among the key regulators of cancer differentiation states.…”

Section: Cell-autonomous Role Of Hs and Hspgs In Cancer Initiation Anmentioning

confidence: 64%

Heparan Sulfate and Heparan Sulfate Proteoglycans in Cancer Initiation and Progression

2018

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Heparan sulfate (HS) are complex unbranched carbohydrate chains that are heavily modified by sulfate and exist either conjugated to proteins or as free, unconjugated chains. Proteins with covalently bound Heparan sulfate chains are termed Heparan Sulfate Proteoglycans (HSPGs). Both HS and HSPGs bind to various growth factors and act as co-receptors for different cell surface receptors. They also modulate the dynamics and kinetics of various ligand-receptor interactions, which in turn can influence the duration and potency of the signaling. HS and HSPGs have also been shown to exert a structural role as a component of the extracellular matrix, thereby altering processes such as cell adhesion, immune cell infiltration and angiogenesis. Previous studies have shown that HS are deregulated in a variety of solid tumors and hematological malignancies and regulate key aspects of cancer initiation and progression. HS deregulation in cancer can occur as a result of changes in the level of HSPGs or due to changes in the levels of HS biosynthesis and remodeling enzymes. Here, we describe the major cell-autonomous (proliferation, apoptosis/senescence and differentiation) and cell-non-autonomous (angiogenesis, immune evasion, and matrix remodeling) roles of HS and HSPGs in cancer. Finally, we discuss therapeutic opportunities for targeting deregulated HS biosynthesis and HSPGs as a strategy for cancer treatment.

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

Cited by 54 publications

References 57 publications

GDE2 is essential for neuronal survival in the postnatal mammalian spinal cord

GDE2 is essential for neuronal survival in the postnatal mammalian spinal cord

Altered expression of miRNAs and methylation of their promoters are correlated in neuroblastoma

Heparan Sulfate and Heparan Sulfate Proteoglycans in Cancer Initiation and Progression

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