Globoside promotes activation of ERK by interaction with the epidermal growth factor receptor

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Background: 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 are so far unknown. Methods: 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, wound assay, western blotting, and RTK array analysis. The functional role of GM was determined by the exogenous addition of various GSLs, and an assay utilizing GSL-coated latex beads. Results: 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, and GD1a). The GSL-coated bead assay indicated that Gb4 forms a complex with EGFR, but not with other RTKs. Taken together, Gb4 promotes activation of EGFR-induced ERK signaling through direct interaction with EGER. General significance: A globo-series GSL, Gb4, promotes EGFR-induced MAPK signaling, resulting in cancer cell proliferation. These findings suggest a possible application of GM in cancer diagnostics and drug targeting. (C) 2012 Elsevier B.V. All rights reserved.
Publisher
ELSEVIER SCIENCE BV
Issue Date
2012-07
Language
English
Article Type
Article
Keywords

MONOCLONAL-ANTIBODY; CELL MOTILITY; GANGLIOSIDE; GLYCOSPHINGOLIPIDS; GLYCOSYNAPSE; PHOSPHORYLATION; DIMERIZATION; ADHESION; ANTIGEN; BINDING

Citation

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v.1820, no.7, pp.1141 - 1148

ISSN
0304-4165
DOI
10.1016/j.bbagen.2012.04.008
URI
http://hdl.handle.net/10203/101780
Appears in Collection
BS-Journal Papers(저널논문)
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