A novel CDC25A/DYRK2 regulatory switch modulates cell cycle and survival

Maribel Lara-Chica, Alejandro Correa-Sáez, Rafael Jiménez-Izquierdo, Martín Garrido-Rodríguez, Francisco J. Ponce, Rita Moreno, Kimberley Morrison, Chiara Di Vona, Krisztina Arató, Carla Jiménez-Jiménez, Rosario Morrugares, M. Lienhard Schmitz, Susana de la Luna, Laureano de la Vega, Marco A. Calzado (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

2 Downloads (Pure)

Abstract

The cell division cycle 25A (CDC25A) phosphatase is a key regulator of cell cycle progression that acts on the phosphorylation status of Cyclin-Cyclin-dependent kinase complexes, with an emergent role in the DNA damage response and cell survival control. The regulation of CDC25A activity and its protein level is essential to control the cell cycle and maintain genomic integrity. Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. CDC25A in turn is able to control the phosphorylation of DYRK2 at several residues outside from its activation loop, thus affecting DYRK2 localization and activity. An inverse correlation between DYRK2 and CDC25A protein amounts was observed during cell cycle progression and in response to DNA damage, with CDC25A accumulation responding to the manipulation of DYRK2 levels or activity in either physiological scenario. Functional data show that the pro-survival activity of CDC25A and the pro-apoptotic activity of DYRK2 could be partly explained by the mutual regulation between both proteins. Moreover, DYRK2 modulation of CDC25A expression and/or activity contributes to the DYRK2 role in cell cycle regulation. Altogether, we provide evidence suggesting that DYRK2 and CDC25A mutually control their activity and stability by a feedback regulatory loop, with a relevant effect on the genotoxic stress pathway, apoptosis, and cell cycle regulation.

Original languageEnglish
Number of pages13
JournalCell Death and Differentiation
Early online date6 Aug 2021
DOIs
Publication statusE-pub ahead of print - 6 Aug 2021

Keywords

  • Cell biology
  • Proteins
  • Proteomics

Fingerprint

Dive into the research topics of 'A novel CDC25A/DYRK2 regulatory switch modulates cell cycle and survival'. Together they form a unique fingerprint.

Cite this