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The GSL-Dependent Signaling

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Glycosphingolipids Signaling

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Abstract

GSLs recognize, bind, and interact with PM proteins including growth factor receptors (GFRs), tetraspanins (TSPs), receptor tyrosine kinases (RTKs), integrins, and nonreceptor cytoplasmic kinases including Src kinase family and G proteins in direct or non-direct mode. Such recognition and interaction contribute to the formation of glycosynaptic microdomains or lipid rafts to regulate GSLs-dependent cell behaviors such as attachment, adhesion, endocytosis, growth, and motility [19]. Gangliosides play key roles through glycan-targeted interactions with membrane receptor proteins (Fig. 3.1). In receptor-mediated biological events, they modulate cell-cell interaction frequently exploited by pathogenic agents such as viruses and bacterial toxins. They also modulate phosphorylating molecules via lateral binding to the membrane proteins of cells. For instance, they directly or indirectly inhibit such receptor-associated tyrosine kinases. In some cases, the interaction between specific gangliosides and cell surface receptor proteins needs posttranslational glycosylation of the PM glycoproteins. Such instances can explain the reason why GSLs-glycoproteins interactions are limited to specialized cases, but not to all the proteins. Gangliosides influence signaling of many GFRs which are currently well known. They include tyrosine kinase receptor (Trk) family, fibroblast GFR (FGFR), epidermal GFR (EGFR), basic FGFR (b-FGFR), platelet-derived GFR (PDGFR), nerve GFR (NGFR), insulin-like GFR (IGFR), insulin receptor, IGF-1 receptor, vascular endothelial GFR (VEGFR), glia cell-derived neurotrophic factor (GDNF), bradykinin 2 receptor (B2R), Fas (CD95) receptor, G protein-coupled receptor (GPCR), serotonin receptor, α1-adrenergic receptor (AR), amyloid-β (Aβ), estrogen receptor (ER), hepatocyte GFR (HGFR), transforming growth factor-β (TGF-β), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and ionotropic glutamate receptor (AMPAR). For example, interactions of GM3-EGFR and GM3-specific RTK on cell surfaces are observed only in the glycosylation status of receptor proteins. Therefore, the GM3 seems to interact with N-glycosylated EGFR or glycosylated RTK to downregulate its RTK. However, specific ganglioside GM1 rather potentiates the neuritogenesis activity of neurotrophins, where gangliosides like GM1s enhance neurite genesis and formation in cultured primary neurons and neuroblastoma cells [116]. GM1 also promotes the dopaminergic and GABAnergic neuron functions in cultured mouse mesencephalic cells. Treatment of the central nerve system (CNS) with GM1 mimics the NGF effect on the cholinergic neuronal protection upon cortical damage and the hippocampal regeneration effect of the CNS cells [117]. In the molecular mechanism, it has been suggested that GM1 protects the degenerative neurons by stimulating the Trk NGF receptor which can be applicable for other neurotrophic growth factors [118], promoting MAPKs and cAMP response element-binding (CREB) molecules in the axotomized nerve retinal region and promoting the dimerization of neurotrophic factor, RTK [119]. Of particular interest are some conflicting outcomes having opposite effects of some gangliosides on the same receptors depending on cell type or tissue type. For example, some gangliosides are overexpressed and shed from tumor cells. Such gangliosides bind to normal cells in the tumor microenvironment, altering tumor cells-host cells interactions for the survival environmental of the tumor cells. However, the present chapter focuses on the biological effects.

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  1. Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, SungKyunKwan University, Suwon, Korea (Republic of)

    Cheorl-Ho Kim

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Kim, CH. (2020). The GSL-Dependent Signaling. In: Glycosphingolipids Signaling. Springer, Singapore. https://doi.org/10.1007/978-981-15-5807-8_3

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