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Transcription-Dependent Epidermal Growth Factor Receptor Activation by Hepatocyte Growth Factor

2008; American Association for Cancer Research; Volume: 6; Issue: 1 Linguagem: Inglês

10.1158/1541-7786.mcr-07-0236

1557-3125

Thomas E. Reznik, Yingying Sang, Yongxian Ma, Roger Abounader, Eliot M. Rosen, Shuli Xia, John Laterra,

HER2/EGFR in Cancer Research

Abstract The mechanisms and biological implications of coordinated receptor tyrosine kinase coactivation remain poorly appreciated. Epidermal growth factor receptor (EGFR) and c-Met are frequently coexpressed in cancers, including those associated with hepatocyte growth factor (HGF) overexpression, such as malignant astrocytoma. In a previous analysis of the HGF-induced transcriptome, we found that two EGFR agonists, transforming growth factor-α and heparin-binding epidermal growth factor–like growth factor (HB-EGF), are prominently up-regulated by HGF in human glioma cells. We now report that stimulating human glioblastoma cells with recombinant HGF induces biologically relevant EGFR activation. EGFR phosphorylation at Tyr845 and Tyr1068 increased 6 to 24 h after cell stimulation with HGF and temporally coincided with the induction of transforming growth factor-α (∼5-fold) and HB-EGF (∼23-fold) expression. Tyr845 and Tyr1068 phosphorylation, in response to HGF, was inhibited by cycloheximide and actinomycin D, consistent with a requirement for DNA transcription and RNA translation. Specifically, blocking HB-EGF binding to EGFR with the antagonist CRM197 inhibited HGF-induced EGFR phosphorylation by 60% to 80% and inhibited HGF-induced S-G2-M transition. CRM197 also inhibited HGF-induced anchorage-dependent cell proliferation but had no effect on HGF-mediated cytoprotection. These findings establish that EGFR can be activated with functional consequences by HGF as a result of EGFR ligand expression. This transcription-dependent cross-talk between the HGF receptor c-Met and EGFR expands our understanding of receptor tyrosine kinase signaling networks and may have considerable consequences for oncogenic mechanisms and cancer therapeutics. (Mol Cancer Res 2008;6(1):139–50)