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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.
Highlights
The cell division cycle-25 (CDC25) family of dual-specificity phosphatases has a key role in controlling cell cycle progression by acting on the phosphorylation status of cyclin-dependent kinases (CDKs) [1, 2]
Given its in the presence of the AS-kinase 1NM-PP1 inhibitor, with a strong essential role in cell-cycle progression, we focused on studying the impact on cell division cycle 25A (CDC25A)-dependent activities as shown by the CDK1 functional interaction between the two proteins
We evaluated the effect of studies showed that CDC25A protein levels were reduced in the Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) small molecule inhibitors
Summary
The cell division cycle-25 (CDC25) family of dual-specificity phosphatases has a key role in controlling cell cycle progression by acting on the phosphorylation status of cyclin-dependent kinases (CDKs) [1, 2]. CDC25A dephosphorylates several CDKs regulating early G1/S transition and late G2/M [4]. CDC25A is considered an oncogene, as its overexpression correlates with tumoral development in many cancer types [5,6,7,8,9] and is associated with alterations in relevant oncogenic pathways [10, 11]. CDC25A dysregulation is often related to cell cycle alterations and apoptosis inhibition, supporting the importance of tight control. CDC25A protein levels are subject to post-translational regulation, during the cell cycle by the ubiquitin–proteasome-dependent pathway. While Cyclin E/CDK2mediated phosphorylation increases CDC25A phosphatase activity during the S phase, Cyclin B/CDK1 mediated phosphorylation at
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