Stress-induced nuclear translocation of CDK5 suppresses neuronal death by downregulating ERK activation via VRK3 phosphorylation

Abstract

Although extracellular signal-related kinase 1/2 (ERK 1/2) activity is generally associated with cell survival, prolonged ERK activation induced by oxidative stress also mediates neuronal cell death. Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation. Overexpression of VRK3 protected human neuroblastoma SH-SY5Y cells against hydrogen peroxide (H2O2)-induced apoptosis. However the CDK5 was unable to phosphorylate mutant VRK3, and thus the mutant forms of VRK3 could not attenuate apoptotic process. Suppression of CDK5 activity results in increase of ERK activation and elevation of proapoptotic protein Bak expression in mouse cortical neurons. Results from VRK3-deficient neurons were further confirmed the role of VRK3 phosphorylation in H2O2-evoked ERK regulation. Importantly, we showed an association between phospho-VRK3 levels and the progression of human Alzheimer’s disease (AD) and Parkinson’s disease (PD). Together our work reveals endogenous protective mechanism against oxidative stress-induced neuronal cell death and suggest VRK3 as a potential therapeutic target in neurodegenerative diseases.

Roscovitine, a CDK5 Inhibitor, Alleviates Sevoflurane-Induced Cognitive Dysfunction via Regulation Tau/GSK3β and ERK/PPARγ/CREB Signaling

“…We also found that upregulation of phosphorylated ERK1/2 promotes neuronal survival [18]. In the present study, we found that ERK1/2 phosphorylation is regulated by CDK5 and is inhibited by sevoflurane-induced CDK5 activation, in agreement with a previous report [27]. Activated ERK1/2 can phosphorylate and activate PPARγ and CREB and thereby abrogate sevoflurane-induced, CDK5-mediated neuronal injury.…”

VRK3-mediated nuclear localization of HSP70 prevents glutamate excitotoxicity-induced apoptosis and Aβ accumulation via enhancement of ERK phosphatase VHR activity

“…Several studies demonstrate that the upregulation of HSPs influences the progression of neurodegenerative disorders5657 and protects against disease-associated toxicity in several neurodegenerative conditions171820. Moreover, recently it has been reported that cyclin-dependent kinase 5-mediated phosphorylation of VRK3 at Ser 108 suppresses oxidative stress-induced prolonged ERK activation and subsequent cell death58. The present study investigated endogenous protective mechanisms mediated by HSP70 and VRK3 against glutamate excitotoxicity-induced neuronal cell death.…”

Evaluation of the Antioxidant Activity of the Marine Pyrroloiminoquinone Makaluvamines

“…To determine the neuroprotective effect of the compound in SHSY5Y cells, we co-incubated the compound with H 2 O 2 for 6 h [22,23]. In all the assays, Vitamin E was added as a positive control in order to compare the antioxidant activity of compound 5 .…”