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

2007-09-01   Monserrat Sanchez-Cespedes 

Molecular Pathology Program, Spanish National Cancer Center (cnio), Melchor Fernandez Almagro, 3, 28029 Madrid, Spain

Identity

HGNC
LOCATION
12q24.23
LOCUSID
ALIAS
AMPK,HAMPKb

DNA/RNA

Atlas Image
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.

Proteins

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.

Implicated in

Bibliography

Pubmed IDLast YearTitleAuthors
174094112007The 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 et al
86214991996Non-catalytic beta- and gamma-subunit isoforms of the 5'-AMP-activated protein kinase.Gao G et al
129600152003Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status.Hardie DG et al
145113942003Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade.Hawley SA et al
146518492003TSC2 mediates cellular energy response to control cell growth and survival.Inoki K et al
127710252003AMPK-beta1 subunit is a p53-independent stress responsive protein that inhibits tumor cell growth upon forced expression.Li J et al
93059091997Posttranslational modifications of the 5'-AMP-activated protein kinase beta1 subunit.Mitchelhill KI et al
127478372003AMPK beta subunit targets metabolic stress sensing to glycogen.Polekhina G et al
175990482007A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome.Sanchez-Cespedes M et al
92247081997AMP-activated protein kinase isoenzyme family: subunit structure and chromosomal location.Stapleton D et al
95752011998Identification of a novel AMP-activated protein kinase beta subunit isoform that is highly expressed in skeletal muscle.Thornton C et al
111711042001Post-translational modifications of the beta-1 subunit of AMP-activated protein kinase affect enzyme activity and cellular localization.Warden SM et al
146148282003LKB1 is the upstream kinase in the AMP-activated protein kinase cascade.Woods A et al
127641522003Identification of phosphorylation sites in AMP-activated protein kinase (AMPK) for upstream AMPK kinases and study of their roles by site-directed mutagenesis.Woods A et al

Other Information

Locus ID:

NCBI: 5564
MIM: 602740
HGNC: 9378
Ensembl: ENSG00000111725

Variants:

dbSNP: 5564
ClinVar: 5564
TCGA: ENSG00000111725
COSMIC: PRKAB1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000111725ENST00000229328Q9Y478
ENSG00000111725ENST00000229328A0A024RBN1
ENSG00000111725ENST00000537400F5H4Y8
ENSG00000111725ENST00000540121F5H2X8
ENSG00000111725ENST00000541640Q9Y478
ENSG00000111725ENST00000541640A0A024RBN1
ENSG00000111725ENST00000545223F5H610
ENSG00000111725ENST00000630317F5H4Y8

Expression (GTEx)

0
10
20
30
40
50
60
70
80

Pathways

PathwaySourceExternal ID
Tight junctionKEGGko04530
Circadian rhythmKEGGko04710
Insulin signaling pathwayKEGGko04910
Adipocytokine signaling pathwayKEGGko04920
Tight junctionKEGGhsa04530
Circadian rhythmKEGGhsa04710
Insulin signaling pathwayKEGGhsa04910
Adipocytokine signaling pathwayKEGGhsa04920
Hypertrophic cardiomyopathy (HCM)KEGGko05410
Hypertrophic cardiomyopathy (HCM)KEGGhsa05410
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
FoxO signaling pathwayKEGGhsa04068
Oxytocin signaling pathwayKEGGhsa04921
Oxytocin signaling pathwayKEGGko04921
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
Glucagon signaling pathwayKEGGhsa04922
Glucagon signaling pathwayKEGGko04922
Organelle biogenesis and maintenanceREACTOMER-HSA-1852241
Mitochondrial biogenesisREACTOMER-HSA-1592230
Activation of PPARGC1A (PGC-1alpha) by phosphorylationREACTOMER-HSA-2151209
Signal TransductionREACTOMER-HSA-162582
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
PI3K CascadeREACTOMER-HSA-109704
PKB-mediated eventsREACTOMER-HSA-109703
mTOR signallingREACTOMER-HSA-165159
Energy dependent regulation of mTOR by LKB1-AMPKREACTOMER-HSA-380972
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
TP53 Regulates Metabolic GenesREACTOMER-HSA-5628897
Vesicle-mediated transportREACTOMER-HSA-5653656
Membrane TraffickingREACTOMER-HSA-199991
Translocation of GLUT4 to the plasma membraneREACTOMER-HSA-1445148
Cellular responses to stressREACTOMER-HSA-2262752
MacroautophagyREACTOMER-HSA-1632852
Insulin resistanceKEGGhsa04931
Longevity regulating pathwayKEGGhsa04211
Longevity regulating pathway - multiple speciesKEGGko04213
Longevity regulating pathway - multiple speciesKEGGhsa04213
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756
Apelin signaling pathwayKEGGhsa04371

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA134983031GPAMGenePathwayassociated22722338
PA142672073CRTC2GenePathwayassociated22722338
PA189HMGCRGenePathwayassociated22722338
PA24421ACACAGenePathwayassociated22722338
PA24422ACACBGenePathwayassociated22722338
PA30861MLYCDGenePathwayassociated22722338
PA335SREBF1GenePathwayassociated22722338
PA35879SLC2A4GenePathwayassociated22722338
PA36198STK11GenePathwayassociated22722338
PA37353MLXIPLGenePathwayassociated22722338
PA37935SIRT1GenePathwayassociated22722338
PA450395metforminChemicalPathwayassociated22722338
PA61ATMGenePathwayassociated22722338

References

Pubmed IDYearTitleCitations
218921422011The AMPK signalling pathway coordinates cell growth, autophagy and metabolism.823
180068252007Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells.332
177118462007The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor.291
201037372010AMPK and SIRT1: a long-standing partnership?215
210722122010The association of AMPK with ULK1 regulates autophagy.176
168734122006Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle.158
170281742006Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.152
216701472011Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels.130
181849302008AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5.117
185511302008Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L.115

Citation

Monserrat Sanchez-Cespedes

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

Atlas Genet Cytogenet Oncol Haematol. 2007-09-01

Online version: http://atlasgeneticsoncology.org/gene/44100/prkab1-(protein-kinase-amp-activated-beta-1-non-catalytic-subunit)