How Do Gangliosides Regulate RTKs Signaling?

Abstract

Gangliosides, the glycosphingolipids carrying one or several sialic acid residues, are located on the outer leaflet of the plasma membrane in glycolipid-enriched microdomains, where they interact with molecules of signal transduction pathways including receptors tyrosine kinases (RTKs). The role of gangliosides in the regulation of signal transduction has been reported in many cases and in a large number of cell types. In this review, we summarize the current knowledge on the biosynthesis of gangliosides and the mechanism by which they regulate RTKs signaling.

Figure 1

Biosynthesis pathway for gangliosides. Gangliosides are synthesized by the stepwise addition of monosaccharides to ceramide. The sequential action of ST3Gal V (G_M3 synthase), ST8Sia I (G_D3 synthase), and ST8Sia V (G_T3 synthase) leads to the biosythesis of the precursors of a-, b-, and c-series gangliosides, respectively. The 0-series gangliosides are directly synthesized from lactosylceramide. The code names of gangliosides are according to Svennerholm [1].

Figure 2

Regulation of RTKs activation by gangliosides. RTKs common structure consists in an extracellular domain containing the ligand binding site, a unique transmembrane domain and a cytoplasmic region containing the tyrosine kinase activity (in red). RTKs are activated by the binding of the ligand that induces receptor dimerization and the autophosphorylation of the intracellular domain. Gangliosides can either inhibit (red arrows) or activate (green arrows) of RTKs signaling, depending on gangliosides expression pattern, cell type, and experimental conditions. Three different mechanisms can be involved: ganglioside/ligand interactions, such as FGF/G_M1 interaction, the regulation of receptor demerization as for G_M3 with EGFR, or the regulation of RTKs activity due to the localization inside GEMs as the case for G_M3 with Insulin receptor (IR). Adapted and updated from [7,37].

Figure 3

Activation of c-Met by G_D2 ganglioside. (A) MDA-MB-231 breast cancer cells express mainly G_M3 and G_M2. (B) The expression of the G_D3 synthase induces the accumlation of b- and c-series gangliosides, mainly G_D2. This leads to the activation of c-Met in the absence of HGF and increases proliferation and migration through PI3K/Akt and MEK/Erk pathways. (C) Anti-G_D2 mAb used in competition assays inhibits c-Met phosphorylation and cell proliferation [72,74].