Human VRK2 (Vaccinia-related Kinase 2) Modulates Tumor Cell Invasion by Hyperactivation of NFAT1 and Expression of Cyclooxygenase-2

Vázquez-Cedeira, Marta; Lazo, Pedro A.

doi:10.1074/jbc.m112.404285

Cited by 37 publications

(37 citation statements)

References 67 publications

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“…d Schematic of domain structure of predicted Vrk2 protein. The source of this figure was previous literature [104, 175]. SCZ, schizophrenia; MDD, major depressive disorder; GGE, genetic generalized epilepsy; OPC, oligodendrocyte progenitor cell.…”

Section: Identification Of Vrk2 Variants In Psychiatric Disorders Amomentioning

confidence: 99%

VRK2, a Candidate Gene for Psychiatric and Neurological Disorders

Yue

2018

Complex Psychiatry

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Recent large-scale genetic approaches, such as genome-wide association studies, have identified multiple genetic variations that contribute to the risk of mental illnesses, among which single nucleotide polymorphisms (SNPs) within or near the vaccinia related kinase 2 (VRK2) gene have gained consistent support for their correlations with multiple psychiatric and neurological disorders including schizophrenia (SCZ), major depressive disorder (MDD), and genetic generalized epilepsy. For instance, the genetic variant rs1518395 in VRK2 showed genome-wide significant associations with SCZ (35,476 cases and 46,839 controls, p = 3.43 × 10^–8) and MDD (130,620 cases and 347,620 controls, p = 4.32 × 10^–12) in European populations. This SNP was also genome-wide significantly associated with SCZ in Han Chinese population (12,083 cases and 24,097 controls, p = 3.78 × 10^–13), and all associations were in the same direction of allelic effects. These studies highlight the potential roles of VRK2 in the central nervous system, and this gene therefore might be a good candidate to investigate the shared genetic and molecular basis between SCZ and MDD, as it is one of the few genes known to show genome-wide significant associations with both illnesses. Furthermore, the VRK2 gene was found to be involved in multiple other congenital deficits related to the malfunction of neurodevelopment, adding further support for the involvement of this gene in the pathogenesis of these neurological and psychiatric illnesses. While the precise function of VRK2 in these conditions remains unclear, preliminary evidence suggests that it may affect neuronal proliferation and migration via interacting with multiple essential signaling pathways involving other susceptibility genes/proteins for psychiatric disorders. Here, we have reviewed the recent progress of genetic and molecular studies of VRK2, with an emphasis on its role in psychiatric illnesses and neurological functions. We believe that attention to this important gene is necessary, and further investigations of VRK2 may provide hints into the underlying mechanisms of SCZ and MDD.

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Section: Identification Of Vrk2 Variants In Psychiatric Disorders Amomentioning

confidence: 99%

VRK2, a Candidate Gene for Psychiatric and Neurological Disorders

Yue

2018

Complex Psychiatry

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“…VRK2 also promotes cancer cell invasion by elevating the transcriptional activity of nuclear factor of activated T cells 1 (NFAT1) by VRK2-mediated phosphorylation (17). In addition, VRK2 prevents apoptosis by interacting with Bcl-x L , an antiapoptotic Bcl-2 homology (BH) domain protein, which is involved in BAX gene expression and regulates mitochondrial function (18).…”

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confidence: 99%

Vaccinia-Related Kinase 2 Controls the Stability of the Eukaryotic Chaperonin TRiC/CCT by Inhibiting the Deubiquitinating Enzyme USP25

Kim

Lee

et al. 2015

Molecular and Cellular Biology

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bMolecular chaperones monitor the proper folding of misfolded proteins and function as the first line of defense against mutant protein aggregation in neurodegenerative diseases. The eukaryotic chaperonin TRiC is a potent suppressor of mutant protein aggregation and toxicity in early stages of disease progression. Elucidation of TRiC functional regulation will enable us to better understand the pathological mechanisms of neurodegeneration. We have previously shown that vaccinia-related kinase 2 (VRK2) downregulates TRiC protein levels through the ubiquitin-proteasome system by recruiting the E3 ligase COP1. However, although VRK2 activity was necessary in TRiC downregulation, the phosphorylated substrate was not determined. Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr 680 , Thr 727 , and Ser 745 residues. Impaired USP25 deubiquitinating activity after VRK2-mediated phosphorylation may be a critical pathway in TRiC protein destabilization.

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“…S3B in the supplemental material). On the other hand, VRK2 is a serine-threonine protein kinase known to phosphorylate substrates such as p53 (21), BAF (27), and NFAT1 (28), and the ability of VRK2 to phosphorylate TRiC was of great interest. However, none of the purified HIS-CCTs were phosphorylated by GST-VRK2 (see Fig.…”

Section: Vrk2 and Chaperonin Tric Interactionmentioning

confidence: 99%

“…Because VRK2 has a sequence similar to that of the catalytic domain of vaccinia-related kinase 1 (VRK1), VRK2 also phosphorylates histone H3 (26), p53 (21), and barrier to autointegration factor (BAF) (27), which supposedly compensates for the VRK1 function. Recently, VRK2 was reported to phosphorylate NFAT1, which affects cell invasion through enhanced Cox2 expression (28). However, other VRK2 functions remain largely unexplored because VRK2 substrates have rarely been identified.…”

mentioning

confidence: 99%

Vaccinia-Related Kinase 2 Mediates Accumulation of Polyglutamine Aggregates via Negative Regulation of the Chaperonin TRiC

Kim

Park

Lee

et al. 2014

Molecular and Cellular Biology

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e Misfolding of proteins containing abnormal expansions of polyglutamine (polyQ) repeats is associated with cytotoxicity in several neurodegenerative disorders, including Huntington's disease. Recently, the eukaryotic chaperonin TRiC hetero-oligomeric complex has been shown to play an important role in protecting cells against the accumulation of misfolded polyQ protein aggregates. It is essential to elucidate how TRiC function is regulated to better understand the pathological mechanism of polyQ aggregation. Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not. Interestingly, VRK2-mediated downregulation of TRiC increased aggregate formation of a polyQ-expanded huntingtin fragment. This effect was ameliorated by rescue of TRiC protein levels. Notably, small interference RNA-mediated knockdown of VRK2 enhanced TRiC protein stability and decreased polyQ aggregation. The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.

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Human VRK2 (Vaccinia-related Kinase 2) Modulates Tumor Cell Invasion by Hyperactivation of NFAT1 and Expression of Cyclooxygenase-2

Cited by 37 publications

References 67 publications

<b><i>VRK2</i></b>, a Candidate Gene for Psychiatric and Neurological Disorders

<b><i>VRK2</i></b>, a Candidate Gene for Psychiatric and Neurological Disorders

Vaccinia-Related Kinase 2 Controls the Stability of the Eukaryotic Chaperonin TRiC/CCT by Inhibiting the Deubiquitinating Enzyme USP25

Vaccinia-Related Kinase 2 Mediates Accumulation of Polyglutamine Aggregates via Negative Regulation of the Chaperonin TRiC

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