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

TY - JOUR

T1 - A novel CDC25A/DYRK2 regulatory switch modulates cell cycle and survival

AU - Lara-Chica, Maribel

AU - Correa-Sáez, Alejandro

AU - Jiménez-Izquierdo, Rafael

AU - Garrido-Rodríguez, Martín

AU - Ponce, Francisco J.

AU - Moreno, Rita

AU - Morrison, Kimberley

AU - Di Vona, Chiara

AU - Arató, Krisztina

AU - Jiménez-Jiménez, Carla

AU - Morrugares, Rosario

AU - Schmitz, M. Lienhard

AU - de la Luna, Susana

AU - de la Vega, Laureano

AU - Calzado, Marco A.

N1 - This work was funded by Ministerio de Ciencia e Innovación (SAF2016-75228-R to MAC and BFU2016-76141-P to SdlL) and by Cancer Research UK (C52419/A22869) to LdlV. MLC and ACS were supported by a FPU fellowship (FPU13/03393 and FPU18/00845, respectively) from the Ministerio de Educación y Formación Profesional. © 2021. The Author(s).

PY - 2022/1

Y1 - 2022/1

N2 - 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.

AB - 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.

KW - Cell biology

KW - Proteins

KW - Proteomics

U2 - 10.1038/s41418-021-00845-5

DO - 10.1038/s41418-021-00845-5

M3 - Article

C2 - 34363019

SN - 1350-9047

VL - 29

SP - 105

EP - 117

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

ER -