RT Journal Article
T1 Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2.
A1 Morrugares, Rosario
A1 Correa-Saez, Alejandro
A1 Moreno, Rita
A1 Garrido-Rodriguez, Martin
A1 Muñoz, Eduardo
A1 de la Vega, Laureano
A1 Calzado, Marco A
K1 Cancer
K1 DYRK2
K1 Degradation
K1 Kinase
K1 NOTCH1
K1 Phosphorylation
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.
PB Springer
YR 2019
FD 2019-09-18
LK http://hdl.handle.net/10668/14634
UL http://hdl.handle.net/10668/14634
LA en
NO Morrugares R, Correa-Sáez A, Moreno R, Garrido-Rodríguez M, Muñoz E, de la Vega L, et al. Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2. Cell Mol Life Sci. 2020 Jul;77(13):2621-2639
DS RISalud
RD Aug 23, 2025