TY - JOUR
T1 - Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2
AU - Morrugares, Rosario
AU - Correa-Sáez, Alejandro
AU - Moreno Dorta, Rita
AU - Garrido-Rodríguez, Martín
AU - Muñoz, Eduardo
AU - de la Vega, Laureano
AU - Calzado, Marco A.
N1 - Funding Information:
ACS was supported by a Plan Propio fellowship from the Universidad de Córdoba and FPU fellowship (FPU18/00845) from the Ministerio de Educación y Formación Profesional. This work was funded by Ministerio de Ciencia e Innovación (MICINN, SAF2016-75228-R) grant to MAC and by Cancer Research UK (C52419/A22869) grant to LDLV. Acknowledgements
Publisher Copyright:
© 2019, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
KW - DYRK2
KW - NOTCH1
KW - Degradation
KW - Kinase
KW - Phosphorylation
KW - Cancer
UR - http://www.scopus.com/inward/record.url?scp=85074026636&partnerID=8YFLogxK
U2 - 10.1007/s00018-019-03309-9
DO - 10.1007/s00018-019-03309-9
M3 - Article
C2 - 31605148
SN - 1420-682X
VL - 77
SP - 2621
EP - 2639
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 13
ER -
