Ganglioside GM3 promotes cell migration by regulating MAPK and c-Fos/AP-1

Abstract

Gangliosides have been proposed as modulators of transmembrane signaling. Recently, GM3, a glycosphingolipid containing monosaialic acids, is thought to be one of the key molecules of signal transduction in mammalian cells. In this study, we used mouse embryonic fibroblast cell lines (MEFs) established from sialyltransferase-I knockout mice (GM3 synthase KO mice) to evaluate the regulation of mitogenic signals by gangliosides. Cell proliferation assay revealed a higher growth potential of GM3 KO MEFs. Immunoblots showed upregulation of Ras/Raf/MEK/ERK pathway in GM3 KO MEFs, and these signals resulted in enhanced translocation of ERK into the nuclei. Further, both exogenous and endogenous add-back of GM3 decreased the activities of MAPK in GM3 KO MEFs. In addition, GM3 KO MEFs formed foci in high-density culture condition, and analyses of cell cycle modulators revealed the resistance of GM3 KO MEFs for entering cell cycle arrest. Finally, sustained expressions of c-Fos in GM3 KO MEFs were shown to correlate with DNA-binding activity between c-Fos and AP-1. These results demonstrate that the deletion of sialyltransferase-I changes the character of MEFs to a highly activated state of the MAPK pathway, indicating the critical role of GM3 as a regulator of membranetransmitted signals.

Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling

“…This is consistent with the reciprocal result observed here; CAV1 deficiency reduces GM3 levels. Experiments in Siat9 / (GM3 synthase knock-out) MEFs demonstrated a reduction in GM3 directly correlated with increased cell motility and an up-regulation of the Ras/ Raf/MAP kinase pathway (Hashiramoto et al, 2006). Although it has been shown that different phospholipids differentially affect H-Ras and K-Ras (Kuroda et al, 1996), GM3 has been postulated as a key regulator for cellular signaling pathways, including those mediated by Ras proteins (Garofalo et al, 2002).…”

Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease

“…Increased GSL biosynthesis (59,60) and GSL-mediated promotion of angiogenesis and metastatic tumor growth (6) have been demonstrated in different types of cancers. We have shown that GM3 is the predominant polar GSL produced by both myeloma cell lines and primary myeloma cells from patients with MM.…”

“…Signaling through lipid raft-associated GSLs has been shown to be an important process in many cell types, including myeloid cells, lymphocytes, and osteoclasts (OCs) (4). For example, GM3 has been shown to regulate lipid raft-mediated cell signaling and cellular adhesion in human lymphocytes (5)(6)(7). Increased synthesis of GM3 is also a defining characteristic that marks the differentiation and maturation of myeloid lineage precursors into monocytes and macrophages, a process that can be promoted by addition of GM3 (8).…”

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

“…in modulation of membrane-bound enzymes and ion-channels, cell-adhesion, neuritogenesis and membrane stability (Hakomori, 2003;Hashiramoto et al, 2006;Ledeen and Wu, 2006;Salazar et al, 2004;Sohn et al, 2006;Susuki et al, 2007;Wu et al, 2007;Yates and Rampersaud, 1998). Furthermore, anti-ganglioside autoimmunity and ganglioside turnover deficits cause neurological disorders (Ang et al, 2004;Maegawa et al, 2006;Simpson et al, 2004;Willison and Yuki, 2002).…”