FGFR1 induces RSK-dependent non-canonical activation of EphA2 during EMT

Epithelial-to-mesenchymal transition (EMT) plays crucial roles in tumor progression, including cancer cell migration. Non-canonical phosphorylation of the receptor tyrosine kinase EphA2 at Ser-897 via the ERK-RSK pathway also induces cancer cell migration. This non-canonically phosphorylated form of EphA2 has been observed in mesenchymal cells and reported to maintain the functional properties of mesenchymal cells; however, the mechanism of this phosphorylation during EMT remains unclear. We herein demonstrated that level of Ser-897-phosphorylated EphA2 was increased during EMT through the FGFR1-ERK-RSK pathway. EphA2 mRNA expression was also induced, suggesting its modulation by Snail, Slug, and ZEB1. Furthermore, the FGFR1-EphA2 axis promoted cell motility and contributed to poor prognosis in lung adenocarcinoma. Collectively, these results suggest the importance of FGFR1 as a regulator of non-canonical EphA2 activation during EMT.