Erk2 but not Erk1 regulates crosstalk between Met and EGFR in squamous cell carcinoma cell lines.

Abstract

BACKGROUND:

Squamous cell carcinoma (SCC) is the most common type of tongue and larynx cancer and a common type of lung cancer. In this study, we attempted to specifically evaluate the signaling pathway underlying HGF/Met induced EGFR ligand release in SSCs. The Met proto-oncogene encodes for a tyrosine kinase receptor which is often hyperactivated in human cancers. Met activation correlates with poor patient outcome. Several studies revealed a role of Met in receptor-crosstalk inducing either activation of other receptors, or inducing their resistance to targeted cancer treatments. In an epithelial tumor cell line screen we recently showed that the Met ligand HGF blocks the EGFR tyrosine kinase and at the same time activates transcriptional upregulation and accumulation in the supernatant of the EGFR ligand amphiregulin (Oncogene 32:3846-56, 2013). In the present work we describe the pathway responsible for the amphiregulin induction.

FINDINGS:

Amphiregulin is transcriptionally upregulated and is released into the supernatant. We show that Erk2 but not Erk1 mediates amphiregulin upregulation upon treatment with monocyte derived HGF. A siRNA knockdown of Erk2 completely abolishes amphiregulin release in squamous cell carcinomas.

CONCLUSIONS:

These results identify Erk2 as the key downstream signal transducer between Met activation and EGFR ligand upregulation in squamous cell carcinoma cell lines derived from tongue, larynx and lung.

• Authors: Simone Gusenbauer, Emanuele Zanucco, Pjotr Knyazev, Axel Ullrich
• Journal: Molecular cancer (Mol Cancer) Vol. 14 Pg. 54 (Mar 04 2015) ISSN: 1476-4598 [Electronic] England
• PMID: 25884419 (Publication Type: Journal Article)

Chemical References

• Amphiregulin
• MAS1 protein, human
• Proto-Oncogene Mas
• Hepatocyte Growth Factor
• ErbB Receptors
• Proto-Oncogene Proteins c-met
• Receptor, ErbB-2
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Amphiregulin (metabolism)
• Carcinoma, Squamous Cell (metabolism)
• Cell Communication
• Cell Line, Tumor
• Endothelial Cells (metabolism)
• ErbB Receptors (metabolism)
• Hepatocyte Growth Factor (pharmacology)
• Humans
• MAP Kinase Signaling System (drug effects)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3
• Models, Biological
• Paracrine Communication
• Protein Binding
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-met (metabolism)
• Receptor, ErbB-2 (metabolism)