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

Rosario Morrugares1,2,3, Alejandro Correa-Sáez1,2,3, Rita Moreno4

  • 1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Avda. Menéndez Pidal s/n. 14004, Córdoba, Spain.

Cellular and Molecular Life Sciences : CMLS
|October 13, 2019
PubMed

Insights

DYRK2 phosphorylates the NOTCH1 intracellular domain (Notch1-IC) in response to chemotherapy, promoting its degradation. This novel mechanism impacts cancer cell viability and invasion, offering new therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Signaling

Background:

  • NOTCH1 signaling is crucial for cell growth and angiogenesis, making it a target for cancer therapy.
  • NOTCH1 intracellular domain (Notch1-IC) stability is regulated by post-translational modifications, particularly FBXW7-mediated degradation.
  • Phosphorylation at Thr-2512 is a prerequisite for Notch1-IC degradation.

Purpose of the Study:

  • To identify novel regulatory mechanisms of the NOTCH1 signaling pathway.
  • To investigate the role of DYRK2 in NOTCH1 regulation in response to chemotherapeutic agents.
  • To elucidate the impact of DYRK2-mediated NOTCH1 regulation on cancer cell behavior.

Main Methods:

  • Investigated DYRK2's role in NOTCH1 phosphorylation and degradation.
  • Utilized chemotherapeutic agents to induce NOTCH1 pathway modulation.
  • Assessed the effects of DYRK2 regulation on cancer cell viability, motility, and invasion.

Main Results:

  • DYRK2 phosphorylates Notch1-IC at Thr-2512 in response to chemotherapeutic agents.
  • This phosphorylation facilitates FBXW7 ubiquitin ligase-mediated proteasomal degradation of Notch1-IC.
  • DYRK2-mediated regulation of NOTCH1 impacts cancer cell viability, motility, and invasion.

Conclusions:

  • A novel DYRK2-dependent mechanism regulates NOTCH1 signaling pathway.
  • This pathway modulation affects cancer cell phenotypes, suggesting therapeutic potential.
  • Understanding this novel NOTCH1 regulation mechanism enhances insights into cancer biology.
Keywords:
CancerDYRK2DegradationKinaseNOTCH1Phosphorylation

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