G2Cdb::Gene report

Gene id
G00002539
Gene symbol
BRSK1 (HGNC)
Species
Homo sapiens
Description
BR serine/threonine kinase 1
Orthologue
G00001290 (Mus musculus)

Databases (7)

Gene
ENSG00000160469 (Ensembl human gene)
84446 (Entrez Gene)
1283 (G2Cdb plasticity & disease)
BRSK1 (GeneCards)
Literature
609235 (OMIM)
Marker Symbol
HGNC:18994 (HGNC)
Protein Sequence
Q8TDC3 (UniProt)

Synonyms (1)

  • KIAA1811

Literature (14)

Pubmed - other

  • SADB phosphorylation of gamma-tubulin regulates centrosome duplication.

    Alvarado-Kristensson M, Rodríguez MJ, Silió V, Valpuesta JM and Carrera AC

    Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain. maria.alvarado-kristensson@med.lu.se

    Symmetrical cell division requires duplication of DNA and protein content to generate two daughter cells. Centrosomes also duplicate during cell division, but the mechanism controlling this process is incompletely understood. We describe an alternative splice form of SadB encoding a short SADB Ser/Thr kinase whose activity fluctuates during the cell cycle, localizes to centrosomes, and controls centrosome duplication. Reduction of endogenous SADB levels diminished centrosome numbers, whereas enhanced SADB expression induced centrosome amplification. SADB exerted this action through phosphorylation of gamma-tubulin on Ser 131, as expression of a phosphomimetic Ser 131-to-Asp gamma-tubulin mutant alone increased centrosome numbers, whereas non-phosphorylatable Ala 131-gamma-tubulin impaired centrosome duplication. We propose that SADB kinase activity controls centrosome homeostasis by regulating phosphorylation of gamma-tubulin.

    Nature cell biology 2009;11;9;1081-92

  • Genome-wide association studies identify loci associated with age at menarche and age at natural menopause.

    He C, Kraft P, Chen C, Buring JE, Paré G, Hankinson SE, Chanock SJ, Ridker PM, Hunter DJ and Chasman DI

    Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. che@hsph.harvard.edu

    Age at menarche and age at natural menopause are associated with causes of substantial morbidity and mortality such as breast cancer and cardiovascular disease. We conducted a joint analysis of two genome-wide association studies of these two traits in a total of 17,438 women from the Nurses' Health Study (NHS, N = 2,287) and the Women's Genome Health Study (WGHS, N = 15,151). For age at menarche, we identified ten associated SNPs (P = 1 × 10(-7)-3 × 10(-13)) clustered at 6q21 (in or near the gene LIN28B) and 9q31.2 (in an intergenic region). For age at natural menopause, we identified 13 associated SNPs (P = 1 × 10(-7)-1 × 10(-21)) clustered at 20p12.3 (in the gene MCM8), 19q13.42 (in or near the gene BRSK1), 5q35.2 (in or near genes UIMC1 and HK3) and 6p24.2 (in the gene SYCP2L). These newly identified loci might expand understanding of the biological pathways regulating these two traits.

    Funded by: NCI NIH HHS: CA 047988, CA 40356, R01 CA040356, R01 CA047988, U01 CA098233, U01 CA098233-06, U01-CA98233; NHLBI NIH HHS: HL 043851, HL69757, R01 HL043851, U01 HL069757, U19 HL069757

    Nature genetics 2009;41;6;724-8

  • Loci at chromosomes 13, 19 and 20 influence age at natural menopause.

    Stolk L, Zhai G, van Meurs JB, Verbiest MM, Visser JA, Estrada K, Rivadeneira F, Williams FM, Cherkas L, Deloukas P, Soranzo N, de Keyzer JJ, Pop VJ, Lips P, Lebrun CE, van der Schouw YT, Grobbee DE, Witteman J, Hofman A, Pols HA, Laven JS, Spector TD and Uitterlinden AG

    Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

    We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; -0.4 year per T allele (39%); P = 6.3 × 10(-11)), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 × 10(-11)) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 × 10(-8)). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.

    Funded by: Wellcome Trust: 077011

    Nature genetics 2009;41;6;645-7

  • C-terminal phosphorylation of LKB1 is not required for regulation of AMP-activated protein kinase, BRSK1, BRSK2, or cell cycle arrest.

    Fogarty S and Hardie DG

    Division of Molecular Physiology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom.

    The tumor suppressor protein kinase LKB1 exerts its effects by phosphorylating and activating AMP-activated protein kinase (AMPK) and members of the AMPK-related kinase family, such as the brain-specific kinases BRSK1/BRSK2 (SAD-B/SAD-A). LKB1 contains a conserved serine residue near the C terminus (Ser-431 in mouse LKB1) that is phosphorylated by cyclic AMP-dependent protein kinase and p90-RSK. Although some studies suggest that LKB1 is constitutively active and is not rate-limiting for activation of AMPK, others have suggested that phosphorylation of Ser-431 is necessary to allow LKB1 to phosphorylate and activate AMPK and other downstream kinases. Prompted by our discovery of an LKB1 splice variant (LKB1S) that lacks Ser-431, we have reinvestigated this question. In HeLa cells (which lack endogenous LKB1), co-expression with STRADalpha and MO25alpha of wild type LKB1, the S431A or S431E mutants of LKB1, or LKB1(S) gave equal levels of activation of endogenous AMPK. Similarly, recombinant STRADalpha.MO25alpha complexes containing these LKB1 variants were equally effective at phosphorylating and activating AMPK, BRSK1, and BRSK2 in cell-free assays. Finally, all four LKB1 variants and a truncated LKB1 lacking the C-terminal region altogether were equally effective at causing cell cycle arrest when co-expressed with STRADalpha and MO25alpha in the G361 melanoma cell line. Our results do not support the idea that phosphorylation of Ser-431 increases the ability of LKB1 to phosphorylate downstream targets.

    Funded by: Wellcome Trust

    The Journal of biological chemistry 2009;284;1;77-84

  • Investigating the regulation of brain-specific kinases 1 and 2 by phosphorylation.

    Bright NJ, Carling D and Thornton C

    Medical Research Council Cellular Stress Group, MRC Clinical Sciences Centre, Du Cane Road, London, United Kingdom.

    Brain-specific kinases 1 and 2 (BRSK1/2) are AMP-activated protein kinase (AMPK)-related kinases that are highly expressed in mammalian forebrain. Studies using transgenic animal models have implicated a role for these kinases in the establishment of neuronal polarity. BRSK1 and BRSK2 are activated by phosphorylation of a threonine residue in the T-loop activation segment of the kinase domain. In vitro studies have demonstrated that LKB1, an upstream kinase in the AMPK cascade, can catalyze this phosphorylation. However, to date, a detailed comparative analysis of the molecular regulation of BRSK1/2 has not been undertaken. Here we present evidence that excludes another upstream kinase in the AMPK cascade, Ca(2+)/calmodulin-dependent protein kinase kinase beta, from a role in activating BRSK1/2. We show that equivalent mutations in the ubiquitin-associated domains of the BRSK isoforms produce differential effects on the activation of BRSK1 and BRSK2. Contrary to previous reports, activation of cAMP-dependent protein kinase does not affect BRSK1 or BRSK2 activity in mammalian cells. Furthermore, stimuli that activate AMPK had no effect on BRSK1/2. Finally, we provide evidence suggesting that protein phosphatase 2C is a likely candidate for catalyzing the dephosphorylation and inactivation of BRSK1/2.

    Funded by: Medical Research Council: MC_U120027537

    The Journal of biological chemistry 2008;283;22;14946-54

  • Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-linked polyubiquitin chains.

    Al-Hakim AK, Zagorska A, Chapman L, Deak M, Peggie M and Alessi DR

    MRC Protein Phosphorylation Unit, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.

    AMPK (AMP-activated protein kinase)-related kinases regulate cell polarity as well as proliferation and are activated by the LKB1-tumour suppressor kinase. In the present study we demonstrate that the AMPK-related kinases, NUAK1 (AMPK-related kinase 5) and MARK4 (microtubule-affinity-regulating kinase 4), are polyubiquitinated in vivo and interact with the deubiquitinating enzyme USP9X (ubiquitin specific protease-9). Knockdown of USP9X increased polyubiquitination of NUAK1 and MARK4, whereas overexpression of USP9X inhibited ubiquitination. USP9X, catalysed the removal of polyubiquitin chains from wild-type NUAK1, but not from a non-USP9X-binding mutant. Topological analysis revealed that ubiquitin monomers attached to NUAK1 and MARK4 are linked by Lys(29) and/or Lys(33) rather than the more common Lys(48)/Lys(63). We find that AMPK and other AMPK-related kinases are also polyubiquitinated in cells. We identified non-USP9X-binding mutants of NUAK1 and MARK4 and find that these are hyper-ubiquitinated and not phosphorylated at their T-loop residue targeted by LKB1 when expressed in cells, suggesting that polyubiquitination may inhibit these enzymes. The results of the present study demonstrate that NUAK1 and MARK4 are substrates of USP9X and provide the first evidence that AMPK family kinases are regulated by unusual Lys(29)/Lys(33)-linked polyubiquitin chains.

    Funded by: Medical Research Council: MC_U127070193

    The Biochemical journal 2008;411;2;249-60

  • Toward a confocal subcellular atlas of the human proteome.

    Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Björling E, Asplund A, Pontén F, Brismar H, Uhlén M and Andersson-Svahn H

    Department of Biotechnology, AlbaNova University Center, Royal Institute of Technology, SE-106 91 Stockholm, Sweden.

    Information on protein localization on the subcellular level is important to map and characterize the proteome and to better understand cellular functions of proteins. Here we report on a pilot study of 466 proteins in three human cell lines aimed to allow large scale confocal microscopy analysis using protein-specific antibodies. Approximately 3000 high resolution images were generated, and more than 80% of the analyzed proteins could be classified in one or multiple subcellular compartment(s). The localizations of the proteins showed, in many cases, good agreement with the Gene Ontology localization prediction model. This is the first large scale antibody-based study to localize proteins into subcellular compartments using antibodies and confocal microscopy. The results suggest that this approach might be a valuable tool in conjunction with predictive models for protein localization.

    Molecular & cellular proteomics : MCP 2008;7;3;499-508

  • SAD: a presynaptic kinase associated with synaptic vesicles and the active zone cytomatrix that regulates neurotransmitter release.

    Inoue E, Mochida S, Takagi H, Higa S, Deguchi-Tawarada M, Takao-Rikitsu E, Inoue M, Yao I, Takeuchi K, Kitajima I, Setou M, Ohtsuka T and Takai Y

    KAN Research Institute, Kyoto 600-8815, Japan.

    A serine/threonine kinase SAD-1 in C. elegans regulates synapse development. We report here the isolation and characterization of mammalian orthologs of SAD-1, named SAD-A and SAD-B, which are specifically expressed in the brain. SAD-B is associated with synaptic vesicles and, like the active zone proteins CAST and Bassoon, is tightly associated with the presynaptic cytomatrix in nerve terminals. A short conserved region (SCR) in the COOH-terminus is required for the synaptic localization of SAD-B. Overexpression of SAD-B in cultured rat hippocampal neurons significantly increases the frequency of miniature excitatory postsynaptic current but not its amplitude. Introduction of SCR into presynaptic superior cervical ganglion neurons in culture significantly inhibits evoked synaptic transmission. Moreover, SCR decreases the size of the readily releasable pool measured by applying hypertonic sucrose. Furthermore, SAD-B phosphorylates the active zone protein RIM1 but not Munc13-1. These results suggest that mammalian SAD kinase presynaptically regulates neurotransmitter release.

    Neuron 2006;50;2;261-75

  • 14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK.

    Al-Hakim AK, Göransson O, Deak M, Toth R, Campbell DG, Morrice NA, Prescott AR and Alessi DR

    MRC Protein Phosphorylation Unit, MSI/WTB complex, University of Dundee, Dow Street, Dundee, DD1 5EH, UK. a.alhakim@dundee.ac.uk

    The LKB1 tumour suppressor kinase phosphorylates and activates a number of protein kinases belonging to the AMP-activated protein kinase (AMPK) subfamily. We have used a modified tandem affinity purification strategy to identify proteins that interact with AMPKalpha, as well as the twelve AMPK-related kinases that are activated by LKB1. The AMPKbeta and AMPKgamma regulatory subunits were associated with AMPKalpha, but not with any of the AMPK-related kinases, explaining why AMP does not influence the activity of these enzymes. In addition, we identified novel binding partners that interacted with one or more of the AMPK subfamily enzymes, including fat facets/ubiquitin specific protease-9 (USP9), AAA-ATPase-p97, adenine nucleotide translocase, protein phosphatase 2A holoenzyme and isoforms of the phospho-protein binding adaptor 14-3-3. Interestingly, the 14-3-3 isoforms bound directly to the T-loop Thr residue of QSK and SIK, after these were phosphorylated by LKB1. Consistent with this, the 14-3-3 isoforms failed to interact with non-phosphorylated QSK and SIK, in LKB1 knockout muscle or in HeLa cells in which LKB1 is not expressed. Moreover, mutation of the T-loop Thr phosphorylated by LKB1, prevented QSK and SIK from interacting with 14-3-3 in vitro. Binding of 14-3-3 to QSK and SIK, enhanced catalytic activity towards the TORC2 protein and the AMARA peptide, and was required for the cytoplasmic localization of SIK and for localization of QSK to punctate structures within the cytoplasm. To our knowledge, this study provides the first example of 14-3-3 binding directly to the T-loop of a protein kinase and influencing its catalytic activity and cellular localization.

    Journal of cell science 2005;118;Pt 23;5661-73

  • The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

    Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Morrin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J and MGC Project Team

    The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

    Funded by: PHS HHS: N01-C0-12400

    Genome research 2004;14;10B;2121-7

  • Human SAD1 kinase is involved in UV-induced DNA damage checkpoint function.

    Lu R, Niida H and Nakanishi M

    Department of Biochemistry and Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.

    Checkpoint activation by DNA damage during G(2) prevents activation of cyclin B/Cdc2 complexes, and as a consequence, mitotic entry is blocked. Although initiation and maintenance of G(2) arrest are known to be regulated by at least two distinct signaling pathways, including those of p38MAPK and ataxia-telangiectasia-mutated (ATM)- and Rad3-related (ATR)-Chk1 in higher eukaryotes, the actual number of signaling pathways involved in this regulation is still elusive. In the present study, we identified human SAD1 (hsSAD1) by searching a sequence data base. The predicted hsSAD1 protein comprises 778 amino acids and shares significant homology with the fission yeast Cdr2, a mitosis-regulatory kinase, and Caenorhabditis elegans SAD1, a neuronal cell polarity regulator. HsSAD1 transcript was expressed ubiquitously with the highest levels of expression in brain and testis. HsSAD1 specifically phosphorylated Wee1A, Cdc25-C, and -B on Ser-642, Ser-216, and Ser-361 in vitro, respectively. Overexpression of hsSAD1 resulted in an increased phosphorylation of Cdc25C on Ser-216 in vivo. DNA damage induced by UV or methyl methane sulfonate but not by IR enhanced endogenous hsSAD1 kinase activity in a caffeine-sensitive manner and caused translocation of its protein from cytoplasm to nucleus. Overexpression of wild-type hsSAD1 induced G(2)/M arrest in HeLa S2 cells. Furthermore, UV-induced G(2)/M arrest was partially abrogated by the reduced expression of hsSAD1 using small interfering RNA. These results suggest that hsSAD1 acts as checkpoint kinase upon DNA damage induced by UV or methyl methane sulfonate. The identification of this new kinase suggests the existence of an alternative checkpoint pathway other than those of ATR-Chk1 and p38MAPK.

    The Journal of biological chemistry 2004;279;30;31164-70

  • LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1.

    Lizcano JM, Göransson O, Toth R, Deak M, Morrice NA, Boudeau J, Hawley SA, Udd L, Mäkelä TP, Hardie DG and Alessi DR

    MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.

    We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP-activated protein kinase (AMPK). A total of 12 human kinases (NUAK1, NUAK2, BRSK1, BRSK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) are related to AMPK. Here we demonstrate that LKB1 can phosphorylate the T-loop of all the members of this subfamily, apart from MELK, increasing their activity >50-fold. LKB1 catalytic activity and the presence of MO25 and STRAD are required for activation. Mutation of the T-loop Thr phosphorylated by LKB1 to Ala prevented activation, while mutation to glutamate produced active forms of many of the AMPK-related kinases. Activities of endogenous NUAK2, QIK, QSK, SIK, MARK1, MARK2/3 and MARK4 were markedly reduced in LKB1-deficient cells. Neither LKB1 activity nor that of AMPK-related kinases was stimulated by phenformin or AICAR, which activate AMPK. Our results show that LKB1 functions as a master upstream protein kinase, regulating AMPK-related kinases as well as AMPK. Between them, these kinases may mediate the physiological effects of LKB1, including its tumour suppressor function.

    The EMBO journal 2004;23;4;833-43

  • Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.

    Nagase T, Nakayama M, Nakajima D, Kikuno R and Ohara O

    Kazusa DNA Research Institute, Kisarazu, Chiba, Japan. nagase@kazusa.or.jp

    To accumulate information on the coding sequences of unidentified genes, we have carried out a sequencing project of human cDNA clones which encode large proteins. We herein present the entire sequences of 100 cDNA clones of unidentified human genes, named KIAA1776 and KIAA1780-KIAA1878, from size-fractionated cDNA libraries derived from human fetal brain, adult whole brain, hippocampus and amygdala. Most of the cDNA clones to be entirely sequenced were selected as cDNAs which were shown to have coding potentiality by in vitro transcription/translation experiments, and some clones were chosen by using computer-assisted analysis of terminal sequences of cDNAs. Three of these clones (fibrillin2/KIAA1776, MEGF10/KIAA1780 and MEGF11/KIAA1781) were isolated as genes encoding proteins with multiple EGF-like domains by motif-trap screening. The average sizes of the inserts and corresponding open reading frames of eDNA clones analyzed here reached 4.7 kb and 2.4 kb (785 amino acid residues), respectively. From the results of homology and motif searches against the public databases, the functional categories of the predicted gene products of 54 genes were determined; 93% of these predicted gene products (50 gene products) were classified as proteins related to cell signaling/communication, nucleic acid management, or cell structure/motility. To collect additional information on these genes, their expression profiles were also studied in 10 human tissues, 8 brain regions, spinal cord, fetal brain and fetal liver by reverse transcription-coupled polymerase chain reaction, products of which were quantified by enzyme-linked immunosorbent assay.

    DNA research : an international journal for rapid publication of reports on genes and genomes 2001;8;2;85-95

Gene lists (6)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000059 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus 748
L00000061 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus (ortho) 984
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
L00000071 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list (ortho) 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

Cookies Policy | Terms and Conditions. This site is hosted by Edinburgh University and the Genes to Cognition Programme.