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PRKAB1 (protein kinase, AMP-activated, beta 1 non-catalytic subunit)

Written2007-09Monserrat Sanchez-Cespedes
Molecular Pathology Program, Spanish National Cancer Center (cnio), Melchor Fernandez Almagro, 3, 28029 Madrid, Spain

(Note : for Links provided by Atlas : click)

Identity

Other namesAMPK
HAMPKb
HGNC (Hugo) PRKAB1
LocusID (NCBI) 5564
Atlas_Id 44100
Location 12q24.23
Location_base_pair Starts at 120105761 and ends at 120119429 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Centromere-H11-BC040553-PRKAB1-CIT-RAB35-telomere.

DNA/RNA

 
  PRKAB1 gene structure. UTR: untranslated region.
Description The PRKAB1 gene, with a total genomic size of 13639 bp, is composed of 7 coding exons of varying lengths.
Transcription The human PRKAB1 transcript has approximately 2500-bp and contains an open reading frame of 813 bases, resulting in a predicted protein of 270 amino acid residues. PRKAB mRNA is detected in most tissues.

Protein

Description PRKAB1 has a molecular mass of 30382 Da; This protein constitutes a regulatory subunit of the AMP-activated protein kinase (AMPK).
AMPK is an heterotrimer of an alpha catalytic, a beta and a gamma non-catalytic regulatory subunits, each encoded by two or three distinct genes (AMPKalpha1-AMPKalpha2; AMPKbeta1-AMPKbeta2; AMPKgamma1-AMPKgamma2-AMPKgamma3) which have varying tissue and subcellular expression.
Post-translational modifications of PRKAB1 include myristoylation and phosphorylation in vivo at Ser24/25, Ser108 and Ser182. Phosphorylation at Ser108 is required for the activation of the AMPK enzyme, whereas phosphorylation at Ser24/25 and Ser182 affects the localization of the complex.
Expression AMPKbeta1 protein expression is highest in the liver, and testis and low in kidney and skeletal muscle. In contrast, expression of PRKAB2, encoded by a different gene, is higher in skeletal muscle. This indicates a tissue specific pattern of expression of these two regulatory beta subunits.
Localisation AMPKbeta1 localises in the cytoplasm. However nuclear translocation is possible because mutations of Ser24/25 and Ser182 to alanine lead to the redistribution of PRKAB1 to the nucleus.
Function AMPKbeta1, may act as a positive regulator of AMPK activity and it may serve as an adaptor molecule for the catalytic subunit. It has also been reported that AMPKbeta1 contains a glycogen-binding domain (GBD) that may target the heterotrimer to glycogen storage sites.
The heterotrimeric protein AMPK senses low intracellular energy levels upon increased in the AMP/ATP ratio. Binding of AMP results in allosteric activation, inducing phosphorylation on Thr-172 of the AMPKa regulatory subunit (PRKAA) by LKB1 in complex with STE20-related adapter-alpha (STRAD alpha). AMPK activation leads to the modulation of the activity of multiple downstream targets to normalize ATP levels.
Among these substrates is the tuberin protein, the product of the tuberous sclerosis complex 2 gene (TSC2) that upon activation by AMPK represses the activity of the mammalian target of rapamycin, mTOR.
It has been reported that PRKAB1 and PRKAB2 contain a glycogen binding domain that targets AMPK to glycogen.
Moreover, it has been shown that expression of PRKAB1 and PRKAB2 genes, in human cells, may be mediated by p53.
Homology There is a AMPKbeta1 isoform, designated AMPKbeta2, encoded by the PRKAB2 gene. The N-terminal region of beta2 differs significantly from that AMPKbeta1 isoform, suggesting that this region could play a role in isoform-specific AMPK activity.
The AMPKbeta subunit is the mammalian homolog of the S. cerevisiae Sip1p/Sip2p/Gal83p family of proteins that interact with the AMPKa homolog, Snf1p, and are involved in glucose regulation of gene expression.

Mutations

Note No germ-line or somatic mutations have been reported in the PRKAB1 gene.

To be noted

Although PRKAB1 itself does not seem to be directly implicated in human disease, there is an indirect relationship between AMPKbeta and heart disease and cancer due to the implication of other subunits of the AMPK complex or to the implication of other related kinases:

  • AMPK in heart disease:
    Mutations at the PRAAG2 (encoding the gamma2 subunit of AMP-activated protein kinase) causes glycogen overload, Wolff-Parkinson-White syndrome, arrhythmias, and heart failure.

  • AMPK in cancer:
    LKB1 is a serine/threonin kinase that phosphorylates and activates AMPK. Germ-line mutations at LKB1 lead to the cancer-prone syndrome Peutz-Jeghers syndrome whereas somatic mutations are implicated in the development of non-small cell lung cancer.
  • Bibliography

    Non-catalytic beta- and gamma-subunit isoforms of the 5'-AMP-activated protein kinase.
    Gao G, Fernandez CS, Stapleton D, Auster AS, Widmer J, Dyck JR, Kemp BE, Witters LA
    The Journal of biological chemistry. 1996 ; 271 (15) : 8675-8681.
    PMID 8621499
     
    Posttranslational modifications of the 5'-AMP-activated protein kinase beta1 subunit.
    Mitchelhill KI, Michell BJ, House CM, Stapleton D, Dyck J, Gamble J, Ullrich C, Witters LA, Kemp BE
    The Journal of biological chemistry. 1997 ; 272 (39) : 24475-24479.
    PMID 9305909
     
    AMP-activated protein kinase isoenzyme family: subunit structure and chromosomal location.
    Stapleton D, Woollatt E, Mitchelhill KI, Nicholl JK, Fernandez CS, Michell BJ, Witters LA, Power DA, Sutherland GR, Kemp BE
    FEBS letters. 1997 ; 409 (3) : 452-456.
    PMID 9224708
     
    Identification of a novel AMP-activated protein kinase beta subunit isoform that is highly expressed in skeletal muscle.
    Thornton C, Snowden MA, Carling D
    The Journal of biological chemistry. 1998 ; 273 (20) : 12443-12450.
    PMID 9575201
     
    Post-translational modifications of the beta-1 subunit of AMP-activated protein kinase affect enzyme activity and cellular localization.
    Warden SM, Richardson C, O'Donnell J Jr, Stapleton D, Kemp BE, Witters LA
    The Biochemical journal. 2001 ; 354 (Pt 2) : 275-283.
    PMID 11171104
     
    Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status.
    Hardie DG
    Endocrinology. 2003 ; 144 (12) : 5179-5183.
    PMID 12960015
     
    Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade.
    Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Mäkelä TP, Alessi DR, Hardie DG
    Journal of biology. 2003 ; 2 (4) : page 28.
    PMID 14511394
     
    TSC2 mediates cellular energy response to control cell growth and survival.
    Inoki K, Zhu T, Guan KL
    Cell. 2003 ; 115 (5) : 577-590.
    PMID 14651849
     
    AMPK-beta1 subunit is a p53-independent stress responsive protein that inhibits tumor cell growth upon forced expression.
    Li J, Jiang P, Robinson M, Lawrence TS, Sun Y
    Carcinogenesis. 2003 ; 24 (5) : 827-834.
    PMID 12771025
     
    AMPK beta subunit targets metabolic stress sensing to glycogen.
    Polekhina G, Gupta A, Michell BJ, van Denderen B, Murthy S, Feil SC, Jennings IG, Campbell DJ, Witters LA, Parker MW, Kemp BE, Stapleton D
    Current biology : CB. 2003 ; 13 (10) : 867-871.
    PMID 12747837
     
    LKB1 is the upstream kinase in the AMP-activated protein kinase cascade.
    Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D
    Current biology : CB. 2003 ; 13 (22) : 2004-2008.
    PMID 14614828
     
    Identification of phosphorylation sites in AMP-activated protein kinase (AMPK) for upstream AMPK kinases and study of their roles by site-directed mutagenesis.
    Woods A, Vertommen D, Neumann D, Turk R, Bayliss J, Schlattner U, Wallimann T, Carling D, Rider MH
    The Journal of biological chemistry. 2003 ; 278 (31) : 28434-28442.
    PMID 12764152
     
    The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways.
    Feng Z, Hu W, de Stanchina E, Teresky AK, Jin S, Lowe S, Levine AJ
    Cancer research. 2007 ; 67 (7) : 3043-3053.
    PMID 17409411
     
    A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome.
    Sanchez-Cespedes M
    Oncogene. 2007 ; 26 (57) : 7825-7832.
    PMID 17599048
     

    Citation

    This paper should be referenced as such :
    Sanchez-Cespedes, M
    PRKAB1 (protein kinase, AMP-activated, beta 1 non-catalytic subunit)
    Atlas Genet Cytogenet Oncol Haematol. 2008;12(2):151-152.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Genes/PRKAB1ID44100ch12q24.html


    External links

    Nomenclature
    HGNC (Hugo)PRKAB1   9378
    Cards
    AtlasPRKAB1ID44100ch12q24
    Entrez_Gene (NCBI)PRKAB1  5564  protein kinase AMP-activated non-catalytic subunit beta 1
    GeneCards (Weizmann)PRKAB1
    Ensembl hg19 (Hinxton)ENSG00000111725 [Gene_View]  chr12:120105761-120119429 [Contig_View]  PRKAB1 [Vega]
    Ensembl hg38 (Hinxton)ENSG00000111725 [Gene_View]  chr12:120105761-120119429 [Contig_View]  PRKAB1 [Vega]
    ICGC DataPortalENSG00000111725
    TCGA cBioPortalPRKAB1
    AceView (NCBI)PRKAB1
    Genatlas (Paris)PRKAB1
    WikiGenes5564
    SOURCE (Princeton)PRKAB1
    Genomic and cartography
    GoldenPath hg19 (UCSC)PRKAB1  -     chr12:120105761-120119429 +  12q24.1-q24.3   [Description]    (hg19-Feb_2009)
    GoldenPath hg38 (UCSC)PRKAB1  -     12q24.1-q24.3   [Description]    (hg38-Dec_2013)
    EnsemblPRKAB1 - 12q24.1-q24.3 [CytoView hg19]  PRKAB1 - 12q24.1-q24.3 [CytoView hg38]
    Mapping of homologs : NCBIPRKAB1 [Mapview hg19]  PRKAB1 [Mapview hg38]
    OMIM602740   
    Gene and transcription
    Genbank (Entrez)AF022116 AJ224515 AK127820 AK301165 AK312495
    RefSeq transcript (Entrez)NM_006253
    RefSeq genomic (Entrez)NC_000012 NC_018923 NT_029419 NW_004929385
    Consensus coding sequences : CCDS (NCBI)PRKAB1
    Cluster EST : UnigeneHs.741184 [ NCBI ]
    CGAP (NCI)Hs.741184
    Alternative Splicing GalleryENSG00000111725
    Gene ExpressionPRKAB1 [ NCBI-GEO ]   PRKAB1 [ EBI - ARRAY_EXPRESS ]   PRKAB1 [ SEEK ]   PRKAB1 [ MEM ]
    Gene Expression Viewer (FireBrowse)PRKAB1 [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)5564
    GTEX Portal (Tissue expression)PRKAB1
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ9Y478 (Uniprot)
    NextProtQ9Y478  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProQ9Y478
    Splice isoforms : SwissVarQ9Y478 (Swissvar)
    PhosPhoSitePlusQ9Y478
    Domains : Interpro (EBI)AMPK1_CBM    AMPK_beta-1    ASC_dom    Ig_E-set   
    Domain families : Pfam (Sanger)AMPK1_CBM (PF16561)    AMPKBI (PF04739)   
    Domain families : Pfam (NCBI)pfam16561    pfam04739   
    Domain families : Smart (EMBL)AMPKBI (SM01010)  
    DMDM Disease mutations5564
    Blocks (Seattle)PRKAB1
    PDB (SRS)4CFE    4CFF   
    PDB (PDBSum)4CFE    4CFF   
    PDB (IMB)4CFE    4CFF   
    PDB (RSDB)4CFE    4CFF   
    Structural Biology KnowledgeBase4CFE    4CFF   
    SCOP (Structural Classification of Proteins)4CFE    4CFF   
    CATH (Classification of proteins structures)4CFE    4CFF   
    SuperfamilyQ9Y478
    Human Protein AtlasENSG00000111725
    Peptide AtlasQ9Y478
    HPRD04116
    IPIIPI00220409   IPI01013083   IPI01011405   IPI01011846   
    Protein Interaction databases
    DIP (DOE-UCLA)Q9Y478
    IntAct (EBI)Q9Y478
    FunCoupENSG00000111725
    BioGRIDPRKAB1
    STRING (EMBL)PRKAB1
    ZODIACPRKAB1
    Ontologies - Pathways
    QuickGOQ9Y478
    Ontology : AmiGOprotein kinase activity  AMP-activated protein kinase activity  protein binding  nucleoplasm  cytosol  protein phosphorylation  fatty acid biosynthetic process  cell cycle arrest  signal transduction  positive regulation of gene expression  macroautophagy  protein kinase binding  nucleotide-activated protein kinase complex  regulation of protein kinase activity  protein heterooligomerization  regulation of signal transduction by p53 class mediator  
    Ontology : EGO-EBIprotein kinase activity  AMP-activated protein kinase activity  protein binding  nucleoplasm  cytosol  protein phosphorylation  fatty acid biosynthetic process  cell cycle arrest  signal transduction  positive regulation of gene expression  macroautophagy  protein kinase binding  nucleotide-activated protein kinase complex  regulation of protein kinase activity  protein heterooligomerization  regulation of signal transduction by p53 class mediator  
    Pathways : BIOCARTAChREBP regulation by carbohydrates and cAMP [Genes]    Reversal of Insulin Resistance by Leptin [Genes]   
    Pathways : KEGGFoxO signaling pathway    Circadian rhythm    Insulin signaling pathway    Adipocytokine signaling pathway    Non-alcoholic fatty liver disease (NAFLD)    Hypertrophic cardiomyopathy (HCM)   
    REACTOMEQ9Y478 [protein]
    REACTOME PathwaysR-HSA-5628897 TP53 Regulates Metabolic Genes [pathway]
    REACTOME PathwaysR-HSA-2151209 Activation of PPARGC1A (PGC-1alpha) by phosphorylation [pathway]
    REACTOME PathwaysR-HSA-1445148 Translocation of GLUT4 to the plasma membrane [pathway]
    REACTOME PathwaysR-HSA-1632852 Macroautophagy [pathway]
    REACTOME PathwaysR-HSA-380972 Energy dependent regulation of mTOR by LKB1-AMPK [pathway]
    NDEx Network
    Atlas of Cancer Signalling NetworkPRKAB1
    Wikipedia pathwaysPRKAB1
    Orthology - Evolution
    OrthoDB5564
    GeneTree (enSembl)ENSG00000111725
    Phylogenetic Trees/Animal Genes : TreeFamPRKAB1
    Homologs : HomoloGenePRKAB1
    Homology/Alignments : Family Browser (UCSC)PRKAB1
    Gene fusions - Rearrangements
    Polymorphisms : SNP, variants
    NCBI Variation ViewerPRKAB1 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)PRKAB1
    dbVarPRKAB1
    ClinVarPRKAB1
    1000_GenomesPRKAB1 
    Exome Variant ServerPRKAB1
    ExAC (Exome Aggregation Consortium)PRKAB1 (select the gene name)
    Genetic variants : HAPMAP5564
    Genomic Variants (DGV)PRKAB1 [DGVbeta]
    Mutations
    ICGC Data PortalPRKAB1 
    TCGA Data PortalPRKAB1 
    Broad Tumor PortalPRKAB1
    OASIS PortalPRKAB1 [ Somatic mutations - Copy number]
    Somatic Mutations in Cancer : COSMICPRKAB1 
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    BioMutasearch PRKAB1
    DgiDB (Drug Gene Interaction Database)PRKAB1
    DoCM (Curated mutations)PRKAB1 (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)PRKAB1 (select a term)
    intoGenPRKAB1
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
    Diseases
    DECIPHER (Syndromes)12:120105761-120119429  ENSG00000111725
    CONAN: Copy Number AnalysisPRKAB1 
    Mutations and Diseases : HGMDPRKAB1
    OMIM602740   
    MedgenPRKAB1
    Genetic Testing Registry PRKAB1
    NextProtQ9Y478 [Medical]
    TSGene5564
    GENETestsPRKAB1
    Huge Navigator PRKAB1 [HugePedia]
    snp3D : Map Gene to Disease5564
    BioCentury BCIQPRKAB1
    ClinGenPRKAB1
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD5564
    Chemical/Pharm GKB GenePA33746
    Clinical trialPRKAB1
    Miscellaneous
    canSAR (ICR)PRKAB1 (select the gene name)
    Probes
    Litterature
    PubMed157 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMinePRKAB1
    EVEXPRKAB1
    GoPubMedPRKAB1
    iHOPPRKAB1
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    indexed on : Thu May 26 11:35:14 CEST 2016

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