| Popis: |
Cancer cells balance with the equilibrium of cell death and growth to expand and metastasize. The activity of mammalian sterile20-like kinases MST1/2 has been linked to apoptosis and tumor suppression via YAP/Hippo pathway dependent and independent mechanisms. With a kinase substrate screen we identified here MST1 and MST2 among the top substrates for fibroblast growth factor receptor 4 (FGFR4). In COS-1 cells, MST1 was phosphorylated at Y433 residue in an FGFR4 kinase activity-dependent manner, as assessed by mass spectrometry. Blockade of this phosphorylation by Y433F mutation induced MST1 activation, as reflected by increased autophosphorylation at T183 in FGFR4 overexpressing MDA-MB-231 cells. Importantly, the specific short-term inhibition or knockdown of FGFR4 also led to MST1/2 activation in conjunction with induction of MST1/2-dependent apoptosis in an endogenous model of HER2+breast cancer cells. Moreover, FGFR4 knockdown increased the level of active nuclear MST1 coincidentally with cell polarization and membrane-association of YAP in three-dimensional breast cancer cell spheres. Consistently, FGFR4 overexpression correlated with reduced Hippo pathway-mediated, nuclear translocation-inhibiting YAP phosphorylation, and abysmal HER2+breast carcinoma patient outcome in TCGA cohort. Our results reveal a novel mechanism for FGFR4 oncogenic activity via suppression of the stress-associated MST1/2-dependent apoptosis machinery in the tumor cells with prominent HER/ERBB signaling driven proliferation. |
