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Signaling and Regulation

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

Departments of ¹ Neurology, ² Oncology, and ³ Neuroscience, Johns Hopkins School of Medicine and ⁴ Kennedy Krieger Research Institute, Baltimore, Maryland; Departments of ⁵ Neurology and ⁶ Microbiology, University of Virginia School of Medicine, Charlottesville, Virginia; and ⁷ Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia

Requests for reprints: John Laterra, The Kennedy Krieger Research Institute, 707 N. Broadway, Baltimore, MD 21205. Phone: 443-923-2679; Fax: 443-923-2695. E-mail: Laterra{at}kennedykrieger.org

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- 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- (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)