High expression of the non-receptor tyrosine kinase FER is an independent prognostic factor that correlates with poor survival in breast cancer patients. To investigate whether the kinase activity is essential for FER oncogenic properties, we developed an ATP analogue-sensitive knock-in allele (FERASKI). Specific FER kinase inhibition in MDA-MB-231 cells reduces migration, invasion, and metastasis in a mouse model of breast cancer. Using the FERASKI system, we identify SKI family transcriptional corepressor 1 (SKOR1) as a direct FER kinase substrate. SKOR1 loss phenocopies FER inhibition, leading to impaired proliferation, migration and invasion, and inhibition of breast cancer growth and metastasis formation in mice. We show that the candidate FER phosphorylation residue, SKOR1-Y234, is essential for FER-dependent tumor progression features. Finally, our work suggests that the SKOR1-Y234 residue promotes Smad2/3 signaling through SKOR1 binding to Smad3 attenuation. Our study thus identifies SKOR1 as a mediator of FER-dependent progression of high-risk breast cancers.

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