Ganglioside-mediated modulation of cell growth. Specific effects of GM3 on tyrosine phosphorylation of the epidermal growth factor receptor.

Hanai, Nobuo; Nores, Gustavo A.; MacLeod, Carol L.; Torres-Mendez, C R; Hakomori, Sen‐itiroh

doi:10.1016/s0021-9258(17)35954-9

Cited by 613 publications

(60 citation statements)

References 43 publications

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“…Our strategy circumvents this problem and demonstrates how specific elongated GSL species are essential for the confinement of IGF-1 and EGF signaling to the basal skin compartment. These findings are in line with previous studies demonstrating that GM3 plays an inhibitory role in IGF-1R and EGF-R signaling (Bremer et al, 1986;Dam et al, 2017) and suggest that a lack of elongated GSLs indirectly affects cell-cell adhesion and proliferation (Dahlgaard et al, 2012;Getsios et al, 2009;Simpson et al, 2011).…”

Section: Discussionsupporting

confidence: 92%

“…Changes in intracellular signaling influence cell-cell adhesion, affecting tissue integrity in human skin (Simpson et al, 2011). Therefore, we speculated that a possible explanation for the reduction in cell-cell adhesion in basal cell layers may be aberrant signaling caused by a loss of gangliosides known to inhibit receptor tyrosine kinases, including the highly expressed insulin growth factor (IGF) and epidermal growth factor (EGF) receptors (IGF-R and EGF-R, respectively) (Bremer et al, 1986;Dam et al, 2017). Immunofluorescence confirmed a significant increase in the activity of IGF-R and EGF-R in both UGCG KO and B4GALT5 KO tissues, which was particularly pronounced in basal and several suprabasal cell layers (Figure 2J).…”

Section: Gsls: Critical For Epidermal Differentiation and Barrier Functionmentioning

confidence: 99%

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Essential Functions of Glycans in Human Epithelia Dissected by a CRISPR-Cas9-Engineered Human Organotypic Skin Model

et al. 2020

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Summary The glycome undergoes characteristic changes during histogenesis and organogenesis, but our understanding of the importance of select glycan structures for tissue formation and homeostasis is incomplete. Here, we present a human organotypic platform that allows genetic dissection of cellular glycosylation capacities and systematic interrogation of the roles of distinct glycan types in tissue formation. We used CRISPR-Cas9 gene targeting to generate a library of 3D organotypic skin tissues that selectively differ in their capacity to produce glycan structures on the main types of N- and O-linked glycoproteins and glycolipids. This tissue library revealed distinct changes in skin formation associated with a loss of features for all tested glycoconjugates. The organotypic skin model provides phenotypic cues for the distinct functions of glycoconjugates and serves as a unique resource for further genetic dissection and identification of the specific structural features involved. The strategy is also applicable to other organotypic tissue models.

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Section: Discussionsupporting

confidence: 92%

Section: Gsls: Critical For Epidermal Differentiation and Barrier Functionmentioning

confidence: 99%

Essential Functions of Glycans in Human Epithelia Dissected by a CRISPR-Cas9-Engineered Human Organotypic Skin Model

et al. 2020

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“…A variety of techniques, ranging from the pharmacologic addition of puri®ed gangliosides in vitro, to the addition of ganglioside inhibitors or metabolizers, to transfection of enzymes that modulate ganglioside biosynthesis, have been used to alter the content of membrane gangliosides and address their role in signal transduction. For example, gangliosides GM3 and GT1b inhibit the growth of cultured keratinocytes and keratinocyte-derived cells through a mechanism that involves inhibition of EGF-R tyrosine phosphorylation, whereas ganglioside GM1 has little effect (Bremer et al, 1986;Paller et al, 1993). In contrast, GM1 is a potent inhibitor of platelet-derived growth factor receptor phosphorylation and platelet-derived growth factor induced proliferation of 3T3 cells (Bremer et al, 1984;Yates et al, 1993;Sachinidis et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Ganglioside Modulates Ligand Binding to the Epidermal Growth Factor Receptor

Wang

Rahman

Sun

et al. 2001

Journal of Investigative Dermatology

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Whereas previous investigations have shown that pharmacologic addition of gangliosides inhibits keratinocyte proliferation by downregulating epidermal growth factor receptor phosphorylation, the underlying biochemical basis and physiologic relevance are unknown. Using Scatchard and displacement plots, we have shown that supplemental purified gangliosides decrease the binding of (125)I-labeled epidermal growth factor to keratinocyte-derived SCC12 cells. Conversely, SCC12 cells transfected with sialidase and thus depleted of gangliosides show increased ligand binding to the epidermal growth factor receptor, which is consistent with their increased proliferation in response to epidermal growth factor and transforming growth factor-alpha, and increased phosphorylation of the epidermal growth factor receptor, and downstream signal transduction pathway components. The mechanism of the altered binding appears to involve primarily decreased numbers of available receptors within the intact membrane, but not altered receptor protein expression. These studies provide evidence that the effect of gangliosides on keratinocyte proliferation results, at least in part, from the direct binding of ganglioside to the receptor and disruption of the receptor-ligand interaction. Manipulation of membrane ganglioside content may be a powerful new means to alter epidermal growth factor receptor-dependent cell proliferation.

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“…Although the molecular mechanisms by which specific GSLs contribute to the selfassociative generation or stabilization of signaling microdomains remain elusive, direct interactions between GM3 and RTKs such as EGFR have been functionally and structurally demonstrated [30,[45][46][47][48]. Weak, potentially disruptive binding between EGFR or other RTKs and the alternatively sialylated GSLs produced by GM3SD cells may significantly impact the efficiency of receptor partition into signaling domains, the efficacy of their signaling activity, or the extent of their residence time at the cell surface (Figure 13).…”

Section: Discussionmentioning

confidence: 99%

Neural-specific alterations in glycosphingolipid biosynthesis and cell signaling associated with two human ganglioside GM3 Synthase Deficiency variants

Dookwah

Wagner

Ishihara

et al. 2021

Preprint

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GM3 Synthase Deficiency (GM3SD) is a neurodevelopmental disorder resulting from pathogenic variants in the ST3GAL5 gene, which encodes GM3 synthase, a glycosphingolipid (GSL)-specific sialyltransferase. This enzyme adds a single alpha3-linked sialic acid to the terminal galactose of lactosylceramide (LacCer) to produce the monosialylated ganglioside GM3. In turn, GM3 is extended by other glycosyltransferases to generate nearly all the complex gangliosides enriched in neural tissue. Pathogenic mechanisms that account for neural phenotypes associated with GM3SD are not known. To explore how loss of GM3 impacts neural-specific glycolipid glycosylation and cell signaling, GM3SD patient fibroblasts bearing one of two different ST3GAL5 variants were reprogrammed to induced pluripotent stem cells (iPSCs) and then differentiated to neural crest cells (NCCs). GM3 and GM3-derived gangliosides were undetectable in iPSCs and NCCs from both variants, while LacCer precursor levels were elevated compared to wildtype (WT). NCCs of both variants synthesized elevated levels of neutral lacto- and globo-series, as well as minor alternatively sialylated, GSLs compared to WT. Shifts in ceramide profiles associated with iPSC and NCC GSLs were also detected in GM3SD variants. Altered GSL profiles in the GM3SD cells were accompanied by dynamic changes in the cell surface proteome, protein O-GlcNAcylation, and receptor tyrosine kinase abundance. GM3SD cells also exhibited increased apoptosis and sensitivity to erlotnib, an inhibitor of epidermal growth factor receptor signaling. Pharmacologic inhibition of O-GlcNAcase increased protein O-GlcNAcylation and significantly rescued baseline and erlotnib-induced apoptosis. Collectively, these findings indicate broad effects on cell signaling during differentiation of GM3SD patient-derived iPSCs to NCCs. Thus, human GM3SD cells provide a novel platform to investigate structure/function relationships that connect GSL diversity to cell signaling, cell survival, and neural differentiation.

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Ganglioside-mediated modulation of cell growth. Specific effects of GM3 on tyrosine phosphorylation of the epidermal growth factor receptor.

Cited by 613 publications

References 43 publications

Essential Functions of Glycans in Human Epithelia Dissected by a CRISPR-Cas9-Engineered Human Organotypic Skin Model

Essential Functions of Glycans in Human Epithelia Dissected by a CRISPR-Cas9-Engineered Human Organotypic Skin Model

Ganglioside Modulates Ligand Binding to the Epidermal Growth Factor Receptor

Neural-specific alterations in glycosphingolipid biosynthesis and cell signaling associated with two human ganglioside GM3 Synthase Deficiency variants

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