Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2

Rosario Morrugares, Alejandro Correa-Sáez, Rita Moreno Dorta, Martín Garrido-Rodríguez, Eduardo Muñoz, Laureano de la Vega, Marco A. Calzado (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    19 Citations (Scopus)
    163 Downloads (Pure)

    Abstract

    NOTCH proteins constitute a receptor family with a widely conserved role in cell cycle, growing and development regulation. NOTCH1, the best characterised member of this family, regulates the expression of key genes in cell growth and angiogenesis, playing an essential role in cancer development. These observations provide a relevant rationale to propose the inhibition of the intracellular domain of NOTCH1 (Notch1-IC) as a strategy for treating various types of cancer. Notch1-IC stability is mainly controlled by post-translational modifications. FBXW7 ubiquitin E3 ligase-mediated degradation is considered one of the most relevant, being the previous phosphorylation at Thr-2512 residue required. In the present study, we describe for the first time a new regulation mechanism of the NOTCH1 signalling pathway mediated by DYRK2. We demonstrate that DYRK2 phosphorylates Notch1-IC in response to chemotherapeutic agents and facilitates its proteasomal degradation by FBXW7 ubiquitin ligase through a Thr-2512 phosphorylation-dependent mechanism. We show that DYRK2 regulation by chemotherapeutic agents has a relevant effect on the viability, motility and invasion capacity of cancer cells expressing NOTCH1. In summary, we reveal a novel mechanism of regulation for NOTCH1 which might help us to better understand its role in cancer biology.

    Original languageEnglish
    Pages (from-to)2621-2639
    Number of pages19
    JournalCellular and Molecular Life Sciences
    Volume77
    Issue number13
    Early online date11 Oct 2019
    DOIs
    Publication statusPublished - Jul 2020

    Keywords

    • DYRK2
    • NOTCH1
    • Degradation
    • Kinase
    • Phosphorylation
    • Cancer

    ASJC Scopus subject areas

    • Cellular and Molecular Neuroscience
    • Molecular Medicine
    • Molecular Biology
    • Cell Biology
    • Pharmacology

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