Regulation of Growth Factor Receptors by Gangliosides

Abstract

Since their discovery in the 1940s, gangliosides have been associated with a number of biological processes, such as growth, differentiation, and toxin uptake. Hypotheses about regulation of these processes by gangliosides are based on indirect observations and lack a clear definition of their mechanisms within the cell. The first insights were provided when a reduction in cell proliferation in the presence of gangliosides was attributed to inhibition of the epidermal growth factor receptor (EGFR). Since that initial finding, most, if not all, growth factor receptors have been described as regulated by gangliosides. In this review, we describe the effects of gangliosides on growth factor receptors, beginning with a list of known effects of gangliosides on growth factor receptors; we then present three models based on fibroblast growth factor (FGFR), platelet-derived growth factor receptor (PDGFR), and EGFR. We focus first on ganglioside modulation of ligand binding; second, we discuss ganglioside regulation of receptor dimerization; and third, we describe a model that implicates gangliosides with receptor activation state and subcellular localization. The methodology used to develop the three models may be extended to all growth factor receptors, bearing in mind that the three models may not be mutually exclusive. We believe that gangliosides do not act independently of many well-established mechanisms of receptor regulation, such as clathrin-coated pit internalization and ubiquitination, but that gangliosides contribute to these functions and to signal transduction pathways. We hypothesize a role for the diverse structures of gangliosides in biology through the organization of the plasma membrane into lipid raft microdomains of unique ganglioside composition, which directly affect the signal duration and membrane localization of the growth factor receptor.

GD3 Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation

“…It is commonly known that gangliosides are associated or complexed with signal transducers such as small G-proteins, Src family kinases, tetraspanins, and integrins (28). The modulation of ganglioside expression can therefore have deep effects on receptormediated signaling, notably RTKs, and regulate cell growth through inhibition/activation of signal transduction pathways (15)(16)(17). For example, tyrosine kinase activity of EGFR is inhibited by the monosialoganglioside G M3 through carbohydrate-carbohydrate interactions of G M3 with GlcNAc terminated N-glycan on EGFR, without interfering with EGF binding (29,30).…”

“…Several studies have shown that cellular ganglioside composition can modulate the activity of growth factor receptors, and consequently induce the activation of intracellular molecular pathways (15)(16)(17). In this context, the phosphorylation status of 42 RTKs was simultaneously examined using a phospho-RTK array in MDA-MB-231 cells.…”

Effect of lipid mimetics of GM3 and lyso-GM3 dimer on EGF receptor tyrosine kinase and EGF-induced signal transduction

“…Studies on modulatory effects, initially observed with GM3 on EGFR tyrosine kinase [1], have been extended to effects of GM1, GD1a, GD1b, and GT1b on platelet-derived growth factor receptor [21,24], GM1 and plasmalopsychosine on nerve growth factor receptor [23,25], and GM3 and sialyl-nLc4 on insulin receptors [22,26]. Therefore, such glycosphingolipid effects can be considered as common in growth factor and hormone receptors, in general (for review see [27,28]). …”

Gangliosides as apoptotic signals in ER stress response

“…1 Gangliosides are also key signaling molecules of pivotal biological processes, including cellular recognition and adhesion, receptor signal transduction, growth regulation, and differentiation. [4][5][6] In addition, they are important messengers of the adaptive responses to stress such as apoptosis. Under stress conditions that dramatically increase their intracellular concentration, gangliosides can initiate the induction of an apoptotic program.…”