Epidermal Growth Factor Receptor Potentiates MCM7-Mediated DNA Replication through Tyrosine Phosphorylation of Lyn Kinase in Human Cancers

• EGFR-Lyn axis regulates MCM7-mediated DNA replication licensing
• Lyn-mediated MCM7 Y600 phosphorylation enhances the formation of MCM complex
• EGFR enhances p56Lyn activity via Y32 phosphorylation, which potentiates p-MCM7 Y600
• p-p56Lyn Y32 and p-MCM7 Y600 correlate with poor survival of breast cancer patients

SummaryEpidermal growth factor receptor (EGFR) initiates a signaling cascade that leads to DNA synthesis and cell proliferation, but its role in regulating DNA replication licensing is unclear. Here, we show that activated EGFR phosphorylates the p56 isoform of Lyn, p56Lyn, at Y32, which then phosphorylates MCM7, a licensing factor critical for DNA replication, at Y600 to increase its association with other minichromosome maintenance complex proteins, thereby promoting DNA synthesis complex assembly and cell proliferation. Both p56Lyn Y32 and MCM7 Y600 phosphorylation are enhanced in proliferating cells and correlated with poor survival of breast cancer patients. These results establish a signaling cascade in which EGFR enhances MCM7 phosphorylation and DNA replication through Lyn phosphorylation in human cancer cells.