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)

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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
Number of pages19
JournalCellular and Molecular Life Sciences
Early online date11 Oct 2019
DOIs
Publication statusE-pub ahead of print - 11 Oct 2019

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TYK2 Kinase
Phosphorylation
Neoplasms
Ubiquitin-Protein Ligases
Post Translational Protein Processing
Ligases
Ubiquitin
Cell Cycle
Gene Expression
Growth
Proteins

Keywords

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

Cite this

@article{c7470bca3b544031b857672ff9455ace,
title = "Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2",
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.",
keywords = "DYRK2, NOTCH1, Degradation, Kinase, Phosphorylation, Cancer",
author = "Rosario Morrugares and Alejandro Correa-S{\'a}ez and {Moreno Dorta}, Rita and Mart{\'i}n Garrido-Rodr{\'i}guez and Eduardo Mu{\~n}oz and {de la Vega}, Laureano and Calzado, {Marco A.}",
note = "Funding for this research was provided by: Ministerio de Ciencia, Innovaci{\'o}n y Universidades (SAF2016-75228-R) Universidad de C{\'o}rdoba Ministerio de Educaci{\'o}n y Formaci{\'o}n Profesional (FPU18/00845)",
year = "2019",
month = "10",
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language = "English",
journal = "Cellular and Molecular Life Sciences",
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Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2. / Morrugares, Rosario; Correa-Sáez, Alejandro; Moreno Dorta, Rita; Garrido-Rodríguez, Martín; Muñoz, Eduardo; de la Vega, Laureano; Calzado, Marco A. (Lead / Corresponding author).

In: Cellular and Molecular Life Sciences, 11.10.2019.

Research output: Contribution to journalArticle

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 for this research was provided by: Ministerio de Ciencia, Innovación y Universidades (SAF2016-75228-R) Universidad de Córdoba Ministerio de Educación y Formación Profesional (FPU18/00845)

PY - 2019/10/11

Y1 - 2019/10/11

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

U2 - 10.1007/s00018-019-03309-9

DO - 10.1007/s00018-019-03309-9

M3 - Article

JO - Cellular and Molecular Life Sciences

JF - Cellular and Molecular Life Sciences

SN - 1420-682X

ER -