Neuronal differentiation through GPI-anchor cleavage

Matas-Rico, Elisa; Veen, Michiel van

doi:10.1080/15384101.2016.1259894

Cited by 13 publications

(13 citation statements)

References 8 publications

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“…It will now be important to determine how GDE3 expression and activity are regulated and, furthermore, to explore the substrate selectivity of GDEs in further detail. When regarded in a broader context, the present and previous findings (Matas-Rico et al, 2016a;Matas-Rico et al, 2016b;Park et al, 2013) support the view that vertebrate GDEs have evolved to modulate key signaling pathways and alter cell behavior through selective GPI-anchor cleavage.…”

Section: Resultssupporting

confidence: 83%

“…A possible clue to the mechanism of uPAR release comes from recent studies showing that a member of the glycerophosphodiester phosphodiesterase (GDPD/GDE) family (Corda et al, 2014), termed GDE2, promotes neuronal differentiation by cleaving select GPI-anchored proteins, notably a Notch ligand regulator and heparan sulfate proteoglycans (Matas-Rico et al, 2016a;Matas-Rico et al, 2016b;Park et al, 2013). GDE2, along with GDE3 and GDE6, belongs to a GDE subfamily characterized by six-transmembrane-domain proteins with a conserved catalytic ectodomain (Figure 1a) (Corda et al, 2009;Matas-Rico et al, 2016a).…”

Section: Introductionmentioning

confidence: 99%

“…400 x g at 4 °C for 10 min), the supernatant was evaporated to dryness in a Speedvac at room temperature. The dried extracts were reconstituted in 50 mM ammonium acetate (pH 8.0), centrifuged(20,400 x g at 4 °C for 10 min) and transferred to autosampler vials. Liquid chromatography (LC) was performed using a Dionex Ultimate 3000RSLCnano system (Thermo Fisher Scientific).…”

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Negative regulation of uPAR activity by a GPI-specific phospholipase C

Matas-Rico

et al. 2016

Preprint

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The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins and other receptors. Full-length uPAR is released from the cell surface, but the mechanism and functional significance of uPAR release remain obscure. Here we show that transmembrane glycerophosphodiesterase GDE3 is a GPI-specific phospholipase C that cleaves and releases uPAR with consequent loss of the proteolytic and non-proteolytic activities of uPAR. In breast cancer cells, high GDE3 expression depletes endogenous uPAR resulting in a less transformed phenotype, correlating with higher survival probability in patients. Our results establish GDE3 as a negative regulator of the uPAR signaling network and, more generally, highlight GPI-anchor hydrolysis as a cell-intrinsic mechanism to alter cell behavior.

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Section: Resultssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Negative regulation of uPAR activity by a GPI-specific phospholipase C

Matas-Rico

et al. 2016

Preprint

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“…A possible clue to the mechanism of uPAR release comes from recent studies showing that a member of the glycerophosphodiester phosphodiesterase (GDPD/GDE) family ( Corda et al, 2014 ), termed GDE2, promotes neuronal differentiation by cleaving select GPI-anchored proteins, notably a Notch ligand regulator and heparan sulfate proteoglycans (glypicans) ( Matas-Rico et al, 2016 ; Matas-Rico et al, 2017 ; Park et al, 2013 ). GDE2, along with GDE3 and GDE6, belongs to a GDE subfamily characterized by six-transmembrane-domain proteins with a conserved catalytic ectodomain ( Figure 1A ) ( Corda et al, 2009 ; Matas-Rico et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells

Veen

Matas-Rico

Wetering

et al. 2017

eLife

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The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins. Full-length uPAR is released from the cell surface, but the mechanism and significance of uPAR shedding remain obscure. Here we identify transmembrane glycerophosphodiesterase GDE3 as a GPI-specific phospholipase C that cleaves and releases uPAR with consequent loss of function, whereas its homologue GDE2 fails to attack uPAR. GDE3 overexpression depletes uPAR from distinct basolateral membrane domains in breast cancer cells, resulting in a less transformed phenotype, it slows tumor growth in a xenograft model and correlates with prolonged survival in patients. Our results establish GDE3 as a negative regulator of the uPAR signaling network and, furthermore, highlight GPI-anchor hydrolysis as a cell-intrinsic mechanism to alter cell behavior.

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“…In contrast to the majority of cell surface proteins which associate with cell membrane via stretches of transmembrane hydrophobic amino acids, soluble GPI-anchored proteins (GPI-APs) are attached to the plasma membrane by forming a covalent linkage between their carboxyl-terminus and the glycan moiety of the GPI glycolipid. The GPI anchor can convey additional properties to the attached proteins which may regulate protein sorting, trafficking and dynamics (Kinoshita, Fujita, & Maeda, 2008;Paulick & Bertozzi, 2008;Zurzolo & Simons, 2016), and this highly dynamic mode of cell surface expression plays essential roles in numerous biological processes including neuronal and embryonic development (Matas-Rico, van Veen, & Moolenaar, 2017;Ng et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia‐seizures syndrome 2 (MCAHS2) family pedigree via whole‐exome sequencing

Yang

Wang

Zhuo

et al. 2018

Molec Gen & Gen Med

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BackgroundGlycosylphosphatidylinositol (GPI) anchoring is a special type of protein posttranslational modification, by which proteins with diverse function are attached to cell membrane through a covalent linkage between the protein and the glycolipid. Phosphatidylinositol glycan anchor biosynthesis class A (PIGA) is a key enzyme in GPI anchor biosynthesis, somatic mutations or genetic variants of which have been associated with paroxysmal nocturnal hemoglobinuria (PNH), or PIGA deficiency, respectively. More than 10 PIGA pathogenic or likely pathogenic variants have been reported in a wide spectrum of clinical syndromes of PIGA deficiency, including multiple congenital anomalies hypotonia‐seizures syndrome 2 (MCAHS2).MethodsWhole‐exome sequencing (WES) was performed on two trios, that is., the proband's family and his affected maternal cousin's family, from a nonconsanguineous Chinese family pedigree with hypotonia‐encephalopathy‐seizures disease history and putative X‐linked recessive inheritance. Sanger sequencing for PIGA variant was performed on affected members as well as unaffected members in the family pedigree to verify its familial segregation.ResultsA novel likely pathogenic variant in PIGA was identified through comparative WES analysis of the two affected families. The single‐nucleotide substitution (NC_000023.9:g.15343279T>C) is located in intron 3 of the PIGA gene and within the splice acceptor consensus sequence (NM_002641.3:c.849‐5A>G). Even though we have not performed RNA studies, in silico tools predict that this intronic variant may alter normal splicing, causing a four base pair insertion which creates a frameshift and a premature stop codon at position 297 (NP_002632.1:p.(Arg283Serfs*15)). Sanger sequencing analysis of the extended family members confirmed the presence of the variant and its X‐linked inheritance.Conclusion WES data analysis along with familial segregation of a rare intronic variant are suggestive of a diagnosis of X‐liked PIGA deficiency with clinical features of MCAHS2.

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Neuronal differentiation through GPI-anchor cleavage

Cited by 13 publications

References 8 publications

Negative regulation of uPAR activity by a GPI-specific phospholipase C

Negative regulation of uPAR activity by a GPI-specific phospholipase C

Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells

A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia‐seizures syndrome 2 (MCAHS2) family pedigree via whole‐exome sequencing

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