Ganglioside GM3 blocks the activation of epidermal growth factor receptor induced by integrin at specific tyrosine sites

Xiao Qi Wang, Ping Sun, Amy S. Paller*

*Corresponding author for this work

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

The epidermal growth factor receptor (EGFR) can be activated by both direct ligand binding and cross-talk with other molecules, such as integrins. This integrin-mediated cross-talk with growth factor receptors participates in regulating cell proliferation, survival, migration, and invasion. Previous studies have shown that ligand-dependent EGFR activation is inhibited by GM3, the predominant ganglioside of epithelial cells, but the effect of GM3 on ligand-independent, integrin-EGFR cross-talk is unknown. Using a squamous carcinoma cell line we show that endogenous accumulation of GM3 disrupts the ligand-independent association of the integrin β1 subunit with EGFR and results in inhibition of cell proliferation. Consistently, endogenous depletion of GM3 markedly increases the association of EGFR with tyrosine-phosphorylated integrin β1 and promotes cell proliferation. The ligand-independent stimulation of EGFR does not require focal adhesion kinase phosphorylation or cytoskeletal rearrangement. Stimulation of EGFR and mitogen-activated protein kinase signaling by GM3 depletion involves the phosphorylation of EGFR at tyrosine residues 845, 1068, and 1148 but not 1086 or 1173. The specific blockade of phosphorylation at Tyr-845 with Src family kinase inhibition and at Tyr-1148 with phosphatidylinositol 3-kinase inhibition suggests that GM3 inhibits integrin-induced, ligand-independent EGFR phosphorylation (cross-talk) through suppression of Src family kinase and phosphatidylinositol 3-kinase signaling.

Original languageEnglish (US)
Pages (from-to)48770-48778
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number49
DOIs
StatePublished - Dec 5 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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