The role of the Fer protein-tyrosine kinase in HER2-positive breast cancer
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Fer is a member of a distinct subclass of cytoplasmic protein-tyrosine kinases with homology to a family of adaptor proteins that regulate membrane-cytoskeletal remodeling events, including receptor endocytosis. Fer has been found to promote metastasis using shRNA knockdown and mouse engraftment models of lung cancer and triple-negative breast cancer. Interestingly, in a transgenic mouse model of HER2-positive breast cancer, mice targeted with a kinase-inactivating mutation (ferDR/DR) had delayed tumor onset, suggesting an important role for Fer activity in tumorigenesis. ferDR/DR mammary tumor epithelial cells (MTECs) from these tumors were hyper-sensitized to EGF stimulation, and this was linked to increased rates of EGFR internalization. This study identifies a role for Fer kinase activity in suppressing EGFR mitogenic signaling, as well as metastasis. In vitro experiments were conducted to validate that a rescue of Fer kinase activity in ferDR/DR MTECs suppresses EGF internalization. As this was correlated with a suppressive effect on downstream signaling and cell proliferation, this suggests that the native function of Fer is to negatively regulate transduction of EGFR signals. Next, MTECs were examined in vivo to show that Fer disruption impairs metastasis. When cells were examined in vitro, loss of Fer activity was associated with impaired cell migration and increased susceptibility to anoikis, suggesting that Fer contributes to multiple cellular processes during metastasis. Fer was also examined in a structure-function study by rescuing Fer expression in ferDR/DR MTEC cells using a panel of domain-specific mutants. We showed that Fer activity may be self-regulated by F-BAR domain activity and phosphorylation of Tyr402, as targeted mutations in these motifs impaired both Fer auto-phosphorylation and the ability of the kinase to suppress EGF-linked mitogenic signaling. Together, these results suggest that Fer plays a direct role in HER2-positive breast cancer by both promoting metastasis and by buffering signals originating from EGFR.