BRSK2 is regulated by ER stress in protein level and involved in ER stress-induced apoptosis

Ying-li, Wang; Wan, Bo; Li, Dawei; Zhou, Jun; Li, Ruwei; Bai, Meirong; Chen, Fang; Liu, Yu

doi:10.1016/j.bbrc.2012.06.046

Cited by 16 publications

(13 citation statements)

References 35 publications

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“…BRSK2 encodes brain selective kinase 2, a serine/threonine kinase of the AMPK family that acts as a checkpoint kinase in response to DNA damage induced by UV irradiation. BRSK2 protein levels are down-regulated in response to ER stress and ER stress promotes localization of BRSK2 to the ER [ 9 ]. Knockdown of endogenous BRSK2 expression enhances ER stress-mediated apoptosis in human pancreatic carcinoma and HeLa cells [ 9 ].…”

Section: Resultsmentioning

confidence: 99%

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis

et al. 2015

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Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6–2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk.

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Section: Resultsmentioning

confidence: 99%

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis

et al. 2015

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“…The five newly discovered CREB kinases all have some indirect connections to CREB according to previous studies. BRSK2 is a serine/threonine protein kinase of the CAMK group, and it plays a key role in polarization of neurons and axonogenesis, 41 , 42 cell cycle progress, 43 and insulin secretion. 44 BRSK2 is phosphorylated and activated by liver kinase B1 (LKB1) and AMPK, 34 which are also CREB kinases.…”

Section: Resultsmentioning

confidence: 99%

Identification of Upstream Kinases by Fluorescence Complementation Mass Spectrometry

et al. 2017

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Protein kinases and their substrates comprise extensive signaling networks that regulate many diverse cellular functions. However, methods and techniques to systematically identify kinases directly responsible for specific phosphorylation events have remained elusive. Here we describe a novel proteomic strategy termed fluorescence complementation mass spectrometry (FCMS) to identify kinase–substrate pairs in high throughput. The FCMS strategy employs a specific substrate and a kinase library, both of which are fused with fluorescence complemented protein fragments. Transient and weak kinase–substrate interactions in living cells are stabilized by the association of fluorescence protein fragments. These kinase–substrate pairs are then isolated with high specificity and are identified and quantified by LC–MS. FCMS was applied to the identification of both known and novel kinases of the transcription factor, cAMP response element-binding protein (CREB). Novel CREB kinases were validated by in vitro kinase assays, and the phosphorylation sites were unambiguously located. These results uncovered possible new roles for CREB in multiple important signaling pathways and demonstrated the great potential of this new proteomic strategy.

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“…BRSK2 plays a key role in the polarization of neurons and axonogenesis, cell cycle progression, and insulin secretion (Müller et al 2010; Nie et al 2012; Chen et al 2012) and regulates the reorganization of the actin cytoskeleton. BRSK2 may also play a role in the apoptotic response triggered by endoplasmic reticulum (ER) stress (Wang et al 2012). Eif2ak3, also known as protein kinase R (PKR)-like ER kinase (PERK), phosphorylates and inactivates the alpha subunit of eukaryotic translation-initiation factor 2, leading to rapid reduction of translational initiation and repression of global protein synthesis (Shi et al 1998; Harding et al 1999; Hayes et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Selection of growth-related genes and dominant genotypes in transgenic Yellow River carp Cyprinus carpio L.

Luo

Huang

Zhang

et al. 2018

Funct Integr Genomics

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Transgenic Yellow River carp is characterized by rapid growth rate and high feed-conversion efficiency and exhibits a great application prospect. However, there is still a significant separation of growth traits in the transgenic Yellow River carp family; as such, growth-related genotypes must be screened for molecular marker-assisted selection. In this study, 23 growth-related candidate genes containing 48 SNP markers were screened through bulked segregant analysis (BSA) among transgenic Yellow River carp family members showing significant separation of growth traits. Then, two growth-related genes (Nos. 17 and 14 genes) were identified through combined genome-wide association study (GWAS) of candidate genes and validation of the full-sibling family approach. Nos. 17 and 14 genes encode BR serine/threonine-protein kinase 2 (BRSK2) and eukaryotic translation-initiation factor 2-alpha kinase 3 (Eif2ak3), respectively. The average body weight of three subgroups carrying the genotypes 17GG, 17GG + 14CC, and 17GG + 14TT of these two genes increased by 27.96, 38.28, and 33.72%, respectively, compared with the controls. The proportion of individuals with body weight > 500 g in these subgroups increased by 19.22, 26.82, and 30.92%, respectively. The results showed that appropriate genotype carriers can be selected from the progeny population through BSA sequencing combined with simplified GWAS analysis. Hence, basic population for breeding can be constructed and transgenic Yellow River carp strains with stable production performance and uniform phenotypic properties can be bred.Electronic supplementary materialThe online version of this article (10.1007/s10142-018-0597-9) contains supplementary material, which is available to authorized users.

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BRSK2 is regulated by ER stress in protein level and involved in ER stress-induced apoptosis

Cited by 16 publications

References 35 publications

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis

Identification of Upstream Kinases by Fluorescence Complementation Mass Spectrometry

Selection of growth-related genes and dominant genotypes in transgenic Yellow River carp Cyprinus carpio L.

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