Globoside (Gb4) promotes activation of ERK by interaction with the epidermal growth factor receptor
Published Date:Apr 20 2012
Source:Biochim Biophys Acta. 1820(7):1141-1148.
Chromatography, Thin Layer
Epidermal Growth Factor Receptor
Mitogen-Activated Protein Kinase 3
Receptor, Epidermal Growth Factor
Tumor Cells, Cultured
Pubmed Central ID:PMC3645941
Funding:R01 DK055823/DK/NIDDK NIH HHS/United States
R21 NS079633/NS/NINDS NIH HHS/United States
2R01CK055823/CK/NCEZID CDC HHS/United States
Globoside (Gb4), a globo-series glycosphingolipid (GSL), has been characterized as a stage-specific embryonic antigen (SSEA), and is highly expressed during embryogenesis as well as in cancer tissues. However, the functional role and molecular mechanism of Gb4 is so far unknown.
GSLs were preferentially inhibited by treatment with D-threo-1-ethylenedioxyphenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4), a nanomolar inhibitor of GSL synthesis, in two carcinoma cell lines, HCT116 and MCF7. The effect of EtDO-P4 was examined by MTT assay, FACS analysis, wound assay, western blotting, and RTK array analysis. The functional role of Gb4 was determined by the exogenous addition of various GSLs, and an assay utilizing GSL-coated latex beads.
Both cell lines contained higher levels of neutral GSLs than of sialic acid-containing GSLs. Gb4 was one of the major neutral GSLs. The depletion of total GSLs caused significant reduction of cell proliferation, but had less effect on cell apoptosis or motility. EtDO-P4 treatment also suppressed activation of the epidermal growth factor receptor (EGFR)-induced ERK pathway and various receptor tyrosine kinases (RTKs). The reduced activation of ERK was restored by the exogenous addition of Gb4, but not by the addition of gangliosides (GM1, GM2, GM3, GD1a). The GSL-coated bead assay indicated that Gb4 forms a complex with EGFR, but not with other RTKs.
Gb4 promotes activation of EGFR-induced ERK signaling through direct interaction with EGFR.
A globo-series GSL, Gb4, promotes EGFR-induced MAPK signaling, resulting in cancer cell proliferation. These findings suggest a possible application of Gb4 in cancer diagnostics and drug targeting.
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