EGF induces coalescence of different lipid rafts

Hofman, Erik; Ruonala, Mika O.; Bader, Arjen N.; Heuvel, Dave van den; Voortman, Jarno; Roovers, Rob C.; Verkleij, Arie J.; Gerritsen, Hans C.; Henegouwen, Paul M.P. van Bergen en

doi:10.1242/jcs.028753

Cited by 136 publications

(140 citation statements)

References 59 publications

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“…contact (94). This model is well in line with our earlier findings showing that upon EGF stimulation, the molecular mass of flotillin oligomers increases, most likely due to their coalescence into larger complexes (56).…”

Section: Role Of Flotillins In Egf Receptor and Mitogen Activated Prosupporting

confidence: 91%

Function of Flotillins in Receptor Tyrosine Kinase Signaling and Endocytosis: Role of Tyrosine Phosphorylation and Oligomerization

Kurrle¹,

John²,

Meister³

et al. 2012

Protein Phosphorylation in Human Health

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Section: Role Of Flotillins In Egf Receptor and Mitogen Activated Prosupporting

confidence: 91%

Function of Flotillins in Receptor Tyrosine Kinase Signaling and Endocytosis: Role of Tyrosine Phosphorylation and Oligomerization

Kurrle¹,

John²,

Meister³

et al. 2012

Protein Phosphorylation in Human Health

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“…These data are in good agreement with previous studies showing that under non-stimulated conditions GPI-anchored proteins are highly mobile and form transient homodimers at the plasma membrane [61]. Upon activation or ligand binding, GPI-anchored proteins form stable homodimers and higher order clusters composed of GPI-anchored proteins and other raft-associated proteins [62,63]. Experimentally, clustering of GPIanchored proteins can be induced by addition of antibodies, and leads to activation of downstream signaling pathways [64].…”

Section: Dynamics Of a Model Raft-associated Protein Upon α-Gal A Silsupporting

confidence: 92%

Altered dynamics of a lipid raft associated protein in a kidney model of Fabry disease

Labilloy¹,

Youker²,

Bruns³

et al. 2014

Molecular Genetics and Metabolism

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Accumulation of globotriaosylceramide (Gb3) and other neutral glycosphingolipids with galactosyl residues is the hallmark of Fabry disease, a lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A (α-gal A). These lipids are incorporated into the plasma membrane and intracellular membranes, with a preference for lipid rafts. Disruption of raft mediated cell processes is implicated in the pathogenesis of several human diseases, but little is known about the effects of the accumulation of glycosphingolipids on raft dynamics in the context of Fabry disease. Using siRNA technology, we have generated a polarized renal epithelial cell model of Fabry disease in Madin-Darby canine kidney cells. These cells present increased levels of Gb3 and enlarged lysosomes, and progressively accumulate zebra bodies. The polarized delivery of both raft-associated and raft-independent proteins was unaffected by α-gal A knockdown, suggesting that accumulation of Gb3 does not disrupt biosynthetic trafficking pathways. To assess the effect of α-gal A silencing on lipid raft dynamics, we employed number and brightness (N&B) analysis to measure the oligomeric status and mobility of the model glycosylphosphatidylinositol (GPI)-anchored protein GFP-GPI. We observed a significant increase in the oligomeric size of antibody-induced clusters of GFP-GPI at the plasma membrane of α-gal A silenced cells compared with control cells. Our results suggest that the interaction of GFP-GPI with lipid rafts may be altered in the presence of accumulated Gb3. The implications of our results with respect to the pathogenesis of Fabry disease are discussed.

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“…Our finding that EGFR is associated with the raft domain is in agreement with previous studies when electron microscopy was used (27). Under higher concentrations of EGF, colocalization of EGFR with GD3 was even stronger; that phenomenon can be explained as the effect of an EGF-induced coalescence of lipid raft domains on the membrane structures (19). In that manner, the clustering of EGFR enhanced the signaling platform.…”

Section: Discussionmentioning

confidence: 93%

“…Colocalization and interaction of EGFR with gangliosides in cells have been reported (19). To study how EGFR was associated with GD3, we performed confocal microscopy to detect the localization of EGFR and GD3 in NSCs.…”

Section: Gd3 Interacts With Egfr and Plays A Role In Association Of Ementioning

confidence: 99%

Interaction of ganglioside GD3 with an EGF receptor sustains the self-renewal ability of mouse neural stem cells in vitro

Wang

2013

Proc. Natl. Acad. Sci. U.S.A.

102

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Mounting evidence supports the notion that gangliosides serve regulatory roles in neurogenesis; little is known, however, about how these glycosphingolipids function in neural stem cell (NSC) fate determination. We previously demonstrated that ganglioside GD3 is a major species in embryonic mouse brain: more than 80% of the NSCs obtained by the neurosphere method express GD3. To investigate the functional role of GD3 in neurogenesis, we compared the properties of NSCs from GD3-synthase knockout (GD3S-KO) mice with those from their wild-type littermates. NSCs from GD3S-KO mice showed decreased self-renewal ability compared with those from the wild-type animals, and that decreased ability was accompanied by reduced expression of EGF receptor (EGFR) and an increased degradation rate of EGFR and EGF-induced ERK signaling. We also showed that EGFR switched from the low-density lipid raft fractions in wild-type NSCs to the high-density layers in the GD3S-KO NSCs. Immunochemical staining revealed colocalization of EGFR and GD3, and EGFR could be immunoprecipitated from the NSC lysate with an anti-GD3 antibody from the wild-type, but not from the GD3S-KO, mice. Tracking the localization of endocytosed EGFR with endocytosis pathway markers indicated that more EGFR in GD3S-KO NSCs translocated through the endosomal−lysosomal degradative pathway, rather than through the recycling pathway. Those findings support the idea that GD3 interacts with EGFR in the NSCs and that the interaction is responsible for sustaining the expression of EGFR and its downstream signaling to maintain the selfrenewal capability of NSCs.G angliosides are ubiquitously expressed in all vertebrate cells and are particularly abundant in the nervous system (1). In early mammalian embryonic brain, the pattern of ganglioside expression is limited to simple gangliosides, predominantly GM3 (NeuAcα2-3Galβ1-4Glcβ1-1′Cer) and GD3 (NeuAcα2-8NeuAcα2-3Galβ1-4Glcβ1-1′Cer). In later developmental stages, however, more complex gangliosides prevail, particularly GM1 (Galβ1-3GalNAcβ1-4(NeuAcα2-3)Galβ1-4Glcβ1-1′Cer), GD1a (NeuAcα2-3Galβ1-3GalNAcβ1-4(NeuAcα2-3)Galβ1-4Glcβ1-1′ Cer), GD1b (Galβ1-3GalNAcβ1-4(NeuAcα2-8NeuAcα2-3) Galβ1-4Glcβ1-1′Cer), and GT1b (NeuAcα2-3Galβ1-3GalNAcβ1-4 (NeuAcα2-8NeuAcα2-3)Galβ1-4Glcβ1-1′Cer) (2, 3). Because of the spatiotemporal expression patterns, gangliosides abundant in embryonic brain, such as GD3 and the c-series ganglioside antigen marker A2B5, have been considered to be useful stage-specific markers of early brain development (4, 5). Mounting evidence supports the notion that gangliosides serve regulatory roles in neurogenesis through modulating processes, such as intercellular recognition, interaction, adhesion, reception, and/ or signaling (6-9). Little is known, however, about how glycosphingolipids (GSLs) function in neural stem cell (NSC) fate determination. Investigation of the biological significance of gangliosides has also been greatly facilitated by the analysis of genetically engineered mice deficient in one or more gangl...

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EGF induces coalescence of different lipid rafts

Cited by 136 publications

References 59 publications

Function of Flotillins in Receptor Tyrosine Kinase Signaling and Endocytosis: Role of Tyrosine Phosphorylation and Oligomerization

Function of Flotillins in Receptor Tyrosine Kinase Signaling and Endocytosis: Role of Tyrosine Phosphorylation and Oligomerization

Altered dynamics of a lipid raft associated protein in a kidney model of Fabry disease

Interaction of ganglioside GD3 with an EGF receptor sustains the self-renewal ability of mouse neural stem cells in vitro

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