J. Lipid Res.
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Journal of Lipid Research, Vol. 43, 971-978, June 2002
Copyright © 2002 by Lipid Research, Inc.

Ganglioside GM3 activates ERKs in human lymphocytic cells

Tina Garofalo{dagger}, Maurizio Sorice1,{dagger}, Roberta Misasi{dagger}, Benedetta Cinque*, Vincenzo Mattei{dagger}, Giuseppe M. Pontieri{dagger}, Maria Grazia Cifone* and Antonio Pavan*

* Dipartimento di Medicina Sperimentale, Università di L'Aquila, Via Vetoio Coppito 2, L'Aquila 67100, Italy
{dagger} Dipartimento di Medicina Sperimentale e Patologia, Università di Roma "La Sapienza," Viale Regina Elena 324, Roma 00161, Italy

1 To whom correspondence should be addressed. e-mail: maurizio.sorice{at}uniroma1.it

In this study we analyzed the signaling pathway triggered by GM3 in lymphoblastoid T-cells. In these cells, GM3 induced cPLA2 activation, arachidonic acid release, and PKC-{delta} translocation. In order to clarify the upstream molecular signals triggered by GM3, we analyzed the activation of extracellular signal-regulated kinase (ERK)s, a downstream effector of Ras-regulated cytoplasmic kinase cascade. Our results showed that GM3 treatment led to rapid ERK phosphorylation in lymphoblastoid T-cells, as detected by anti-phospho-p44/42 MAP kinase. Similar findings were found in human peripheral blood lymphocytes. Moreover, we showed that GM3 specifically phosphorylated ERK-2, as revealed by anti-phosphotyrosine reactivity on both cell free lysates and ERKs immunoprecipitates. The role of the CD4 cytoplasmic domain in GM3-triggered signaling pathway was investigated using A2.01/CD4-cyt399 cells, which had been transfected with a mutant form of CD4 lacking the bulk of the cytoplasmic domain. In these cells GM3 induced cPLA2 activation, arachidonic acid release, and PKC-{delta} translocation, but not CD4 endocytosis, indicating that the CD4 cytoplasmic domain plays a key role in GM3-triggered CD4 endocytosis and the GM3-triggered biochemical pathway is upstream of CD4 phosphorylation.

These findings strongly suggest that GM3 triggers a novel signaling pathway involved in the regulation of cellular functions.

Abbreviations: AA, arachidonic acid; AACOCF3, trifluoromethylketone analog of arachidonic acid; cPLA2, cytosolic phospholipase A2; EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; HRP, horseradish peroxidase; NGF, nerve growth factor; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; PBL, peripheral blood lymphocytes; PC, phosphatidylcoline; PKC, protein kinase C

Supplementary key words extracellular signal-regulated kinase • CD4 • lipid domains • glycosphingolipids


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