{"entity": "publication", "iuid": "ec1b23f403e445cda23066b8b96093a0", "timestamp": "2026-08-29T04:16:50.296Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/ec1b23f403e445cda23066b8b96093a0.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/ec1b23f403e445cda23066b8b96093a0"}}, "title": "FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis.", "authors": [{"family": "Turunen", "given": "S Pauliina", "initials": "SP"}, {"family": "von Nandelstadh", "given": "Pernilla", "initials": "P"}, {"family": "\u00d6hman", "given": "Tiina", "initials": "T"}, {"family": "Gucciardo", "given": "Erika", "initials": "E"}, {"family": "Seashore-Ludlow", "given": "Brinton", "initials": "B"}, {"family": "Martins", "given": "Beatriz", "initials": "B"}, {"family": "Rantanen", "given": "Ville", "initials": "V"}, {"family": "Li", "given": "Huini", "initials": "H"}, {"family": "H\u00f6pfner", "given": "Katrin", "initials": "K"}, {"family": "\u00d6stling", "given": "P\u00e4ivi", "initials": "P"}, {"family": "Varjosalo", "given": "Markku", "initials": "M"}, {"family": "Lehti", "given": "Kaisa", "initials": "K"}], "type": "journal article", "published": "2019-12-00", "journal": {"title": "Cell Death Differ.", "issn": "1476-5403", "volume": "26", "issue": "12", "pages": "2577-2593", "issn-l": "1350-9047"}, "abstract": "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-independent and -dependent mechanisms. Using 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 indicated by increased threonine phosphorylation of MST1/2, and the downstream substrate MOB1, in FGFR4-overexpressing T47D and MDA-MB-231 breast cancer cells. Importantly, the specific knockdown or short-term inhibition of FGFR4 in endogenous models of human HER2+ breast cancer cells likewise led to increased MST1/2 activation, in conjunction with enhanced MST1 nuclear localization and generation of N-terminal cleaved and autophosphorylated MST1. Unexpectedly, MST2 was also essential for this MST1/N activation and coincident apoptosis induction, although these two kinases, as well as YAP, were differentially regulated in the breast cancer models analyzed. Moreover, pharmacological FGFR4 inhibition specifically sensitized the HER2+ MDA-MB-453 breast cancer cells, not only to HER2/EGFR and AKT/mTOR inhibitors, but also to clinically relevant apoptosis modulators. In TCGA cohort, FGFR4 overexpression correlated with abysmal HER2+ breast carcinoma patient outcome. Therefore, our results uncover a clinically relevant, targetable mechanism of FGFR4 oncogenic activity via suppression of the stress-associated MST1/2-induced apoptosis machinery in tumor cells with prominent HER/ERBB and FGFR4 signaling-driven proliferation.", "doi": "10.1038/s41418-019-0321-x", "pmid": "30903103", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC7224384"}, {"db": "pii", "key": "10.1038/s41418-019-0321-x"}], "notes": [], "created": "2026-08-20T08:49:08.160Z", "modified": "2026-08-20T08:49:08.203Z"}