SKOR1 mediates FER kinase-dependent invasive growth of breast cancer cells.
Lilian M SluimerEsme BullockMax A K RätzeLotte EnserinkCeline OverbeekeMarten HornsveldValerie G BruntonPatrick W B DerksenSandra TavaresPublished in: Journal of cell science (2023)
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 of FER is essential for its oncogenic properties, we developed an ATP analogue-sensitive knock-in allele (FERASKI). Specific FER kinase inhibition in MDA-MB-231 cells reduces migration and invasion, as well as metastasis when xenografted into a mouse model of breast cancer. Using the FERASKI system, we identified 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 SKOR1 Y234, a candidate FER phosphorylation site, is essential for FER-dependent tumor progression. Finally, our work suggests that the SKOR1 Y234 residue promotes Smad2/3 signaling through SKOR1 binding to Smad3. Our study thus identifies SKOR1 as a mediator of FER-dependent progression of high-risk breast cancers.
Keyphrases
- tyrosine kinase
- protein kinase
- breast cancer cells
- prognostic factors
- poor prognosis
- epidermal growth factor receptor
- epithelial mesenchymal transition
- gene expression
- type diabetes
- induced apoptosis
- genome wide
- transforming growth factor
- dna methylation
- adipose tissue
- cell proliferation
- oxidative stress
- insulin resistance
- cell death
- endoplasmic reticulum stress
- heat shock protein
- free survival