FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis
| Autor: | S. Pauliina Turunen, Beatriz Martins, Erika Gucciardo, Brinton Seashore-Ludlow, Ville Rantanen, Pernilla von Nandelstadh, Kaisa Lehti, Markku Varjosalo, Päivi Östling, Katrin Höpfner, H Li, Tiina Öhman |
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| Přispěvatelé: | Research Programs Unit, University of Helsinki, HUS Helsinki and Uusimaa Hospital District, Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE, Genome-Scale Biology (GSB) Research Program, Medicum, ImmunoViroTherapy Lab, Research Program in Systems Oncology, Kaisa Irene Lehti / Principal Investigator, University Management, Molecular Systems Biology, INDIVIDRUG - Individualized Drug Therapy |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
HIPPO INVASION Apoptosis Serine-Threonine Kinase 3 ACTIVATION PATHWAY 0302 clinical medicine Chlorocebus aethiops Phosphorylation skin and connective tissue diseases Chemistry Kinase Intracellular Signaling Peptides and Proteins 030220 oncology & carcinogenesis COS Cells MCF-7 Cells GROWTH Female Programmed cell death CARCINOMA INHIBITION Kinases Breast Neoplasms Protein Serine-Threonine Kinases Transfection Article 03 medical and health sciences Breast cancer ErbB Cell Line Tumor medicine EXTRACELLULAR-MATRIX KINASE Animals Humans Receptor Fibroblast Growth Factor Type 4 Molecular Biology Protein kinase B IDENTIFICATION Cell Biology Fibroblast growth factor receptor 4 Oncogenes medicine.disease 030104 developmental biology Cancer cell Cancer research 1182 Biochemistry cell and molecular biology 3111 Biomedicine |
| Zdroj: | Cell Death and Differentiation |
| 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-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. |
| Databáze: | OpenAIRE |
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