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GLS2 (Glutaminase 2)

Written2015-12José A Campos-Sandoval, Mercedes Martín-Rufián, Javier Márquez
Canceromics lab, Departamento de Biologia molecular y Bioquimica, Facultad de CIENCIAS, University of Malaga, 29071 Malaga, Spain; jacs@uma.es, mercherub@uma.es, marquez@uma.es.

(Note : for Links provided by Atlas : click)

Identity

Alias_namesglutaminase 2 (liver
Alias_symbol (synonym)GA
GLS
LGA
hLGA
Other aliasPAG (phosphate-activated glutaminase)
GAB
LGA (liver-type glutaminase)
HGNC (Hugo) GLS2
LocusID (NCBI) 27165
Atlas_Id 46328
Location 12q13.3  [Link to chromosome band 12q13]
Location_base_pair Starts at 56470944 and ends at 56488414 bp from pter ( according to hg19-Feb_2009)  [Mapping GLS2.png]
Fusion genes
(updated 2016)
GLS2 (12q13.3) / GLS2 (12q13.3)

DNA/RNA

 
  Genomic structure of GLS2 gene and mRNA transcripts. Introns are depicted as solid orange lines and exons as numbered blue boxes. Dashed red or dotted green lines indicate the exons involved in the generation of GAB and LGA transcripts, respectively. Modified from Márquez et al., BioMol. Concepts, 1, 3-15 (2010).
Description GLS2 gene is composed of 18 exons, with a length of approximately 18 kbases (Pérez-Gómez et al., 2003). Position 56864728 to 56882198, minus strand (NCBI, 27165).
Transcription Two sense GLS2 transcripts have been identified: a long canonical one containing all 18 exons (GAB, 2.4 kb)(Gómez-Fabre et al., 2000) and a short variant (LGA, 1.9 kb) lacking the first exon (Martín-Rufián et al., 2012). LGA transcript appears by alternative transcription initiation and has an alternative promoter, with its transcription start site located at 3-end of first intron of GLS2 gene. Other non-coding transcripts, containing premature stop codons, have been isolated. GLS2 transcription can be regulated by p53 and p63 tumour suppressors (Hu et al., 2010; Suzuki et al., 2010; Giacobbe et al., 2013).
Pseudogene At least one reported pseudogene for GLS2 (GenBank: AF110329.1).

Protein

Note To date, any GLS2 isoform has been isolated from human tissues or cells, so all information about protein structure or posttranslational modifications derive from bioinformatic analysis.
 
  Schematic diagram of GLS2 isoforms showing the localization of predicted domains and motifs by sequence analysis.
Description GAB transcript (1809 bps ORF) codes a 602-residues protein, with a predicted molecular mass of 66309 Da. LGA transcript (1698 bps ORF) codes a 565-residues protein, with a predicted molecular mass of 62496 Da. The precursor of LGA isoform lacks the first 61 residues at the N-terminal region of GAB precursor (coded by exon 1), but it displays an additional extension of 24 residues at the N-terminus coded by an alternative first exon.
GLS2 contains a catalytic domain (glutaminase domain) of approx. 300 residues, 2 ankyrin repeats at the C-terminal region and a consensus sequence of 4 residues at the C-terminal end required for specific interaction with PDZ proteins, as alpha-syntrophin (SNT) and Glutaminase-Interacting Protein (GIP) (Olalla et al., 2001). The N-terminal end (first 14 residues) of GAB precursor contains a putative mitochondrial import presequence (Gómez-Fabre et al., 2000). It is worth mentioning the presence of a consensus LXXLL motif of interaction with nuclear receptors at N-terminal region of GLS2 (Olalla et al., 2002).
Expression Brain, liver, pancreas, human cancer cells (Gómez-Fabre et al., 2000 ; Aledo et al., 2000 ; Pérez-Gómez et al., 2005), cells of immune system (Castell et al., 2004).
Localisation Mitochondrial. A nuclear localization has also been reported for neurons (Olalla el al., 2002).
Function GLS2 (E.C. 3.5.1.2.) catalyzes the hydrolytic deamidation of L-glutamine to form L-glutamate and ammonium, the first step of glutaminolysis. As shown in recent works, GLS2 overexpression in glioblastoma cell lines caused a reversion of their transformed phenotype (Szeliga et al., 2009). This is in agreement with the loss of GLS2 expression in hepatocellular carcinomas (Suzuki et al., 2010) and brain tumours (Szeliga et al., 2005). So, GLS2 may play a role as tumour suppressor, in opposition to that of GLS, regulated by oncogenes and associated to tumorigenesis. However, this behavior of GLS2 is not universal, as there are some types of cancer -like cervical cancer- where upregulation of GLS2 occurs, conferring therapeutic resistance (Xiang et al., 2013).

Implicated in

Note
  
Entity Glioblastoma (WHO grade IV).
Note GLS2 expression is downregulated in highly malignant glioblastoma (Szeliga et al., 2005 and 2009). One of the mechanisms involved in this gene silencing was recently demonstrated to be promoter methylation and not related to the p53 status (Szeliga et al., 2015). Human glioblastoma T98G cells stably transfected with the full GLS2 cDNA coding sequence showed a reversion of their malignant phenotype, including a marked inhibition in growth and proliferation (Szeliga et al., 2009), down-regulation of the expression of DNA-repair gene MGMT and sensitization to alkylating agents (Szeliga et al., 2012). ROS generation by treatment with oxidizing agents synergized with GLS2 overexpression in T98G glioma cells to suppress their malignant properties, including the reduction of cellular mobility (Martín-Rufián et al., 2015).
  
  
Entity Hepatocellular Carcinoma
Note Two research groups identified GLS2 as a target for p53 tumor suppressor gene (Hu et al., 2010; Suzuki et al., 2010). GLS2 is frequently downregulated or repressed in some types of cancer, like human hepatocellular carcinoma (Yuneva et al., 2012). It is remarkable that GLS2 transcripts were almost absent or significantly decreased in hepatocellular carcinomas compared to normal liver tissue, where GLS2 is abundantly expressed (Suzuki et al. 2010). These findings support the hypothesis that repression of GLS2 is a frequent trait associated with tumorigenesis. Hence, the authors suggested a potential tumor suppressor role for GLS2 (Suzuki et al. 2010). Of interest, it has been demonstrated that GLS2 can be transcriptionally regulated by TP63, a transcription factor belonging to the p53 family (Giacobbe et al. 2013).
  
  
Entity Cervical Carcinoma
Note Expression of GLS2 was significantly enhanced in cervical carcinoma and related to therapeutic resistance (Xiang et al., 2013).
  

Bibliography

Identification of two human glutaminase loci and tissue-specific expression of the two related genes
Aledo JC, Gómez-Fabre PM, Olalla L, Má;rquez J
Mamm Genome 2000 Dec;11(12):1107-10
PMID 11130979
 
Granule localization of glutaminase in human neutrophils and the consequence of glutamine utilization for neutrophil activity
Castell L, Vance C, Abbott R, Marquez J, Eggleton P
J Biol Chem 2004 Apr 2;279(14):13305-10
PMID 14722097
 
Molecular cloning, sequencing and expression studies of the human breast cancer cell glutaminase
Gómez-Fabre PM, Aledo JC, Del Castillo-Olivares A, Alonso FJ, Nez De Castro I, Campos JA, Má;rquez J
Biochem J 2000 Jan 15;345 Pt 2:365-75
PMID 10620514
 
p63 regulates glutaminase 2 expression
Giacobbe A, Bongiorno-Borbone L, Bernassola F, Terrinoni A, Markert EK, Levine AJ, Feng Z, Agostini M, Zolla L, Agrò AF, Notterman DA, Melino G, Peschiaroli A
Cell Cycle 2013 May 1;12(9):1395-405
PMID 23574722
 
Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function
Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z
Proc Natl Acad Sci U S A 2010 Apr 20;107(16):7455-60
PMID 20378837
 
Brain glutaminases
Márquez J, Martín-Rufièn M, Segura JA, Matès JM, Campos-Sandoval JA, Alonso FJ
Biomol Concepts 2010 May 1;1(1):3-15
PMID 25961981
 
Both GLS silencing and GLS2 overexpression synergize with oxidative stress against proliferation of glioma cells
Martín-Rufén M, Nascimento-Gomes R, Higuero A, Crisma AR, Campos-Sandoval JA, Gómez-García MC, Cardona C, Cheng T, Lobo C, Segura JA, Alonso FJ, Szeliga M, Albrecht J, Curi R, Márquez J, Colquhoun A, Deberardinis RJ, Matés JM
J Mol Med (Berl) 2014 Mar;92(3):277-90
PMID 24276018
 
The C-terminus of human glutaminase L mediates association with PDZ domain-containing proteins
Olalla L, Aledo JC, Bannenberg G, Márquez J
FEBS Lett 2001 Jan 19;488(3):116-22
PMID 11163757
 
Nuclear localization of L-type glutaminase in mammalian brain
Olalla L, Gutiérrez A, Campos JA, Khan ZU, Alonso FJ, Segura JA, Márquez J, Aledo JC
J Biol Chem 2002 Oct 11;277(41):38939-44
PMID 12163477
 
Co-expression of glutaminase K and L isoenzymes in human tumour cells
Pérez-Gómez C, Campos-Sandoval JA, Alonso FJ, Segura JA, Manzanares E, Ruiz-Sánchez P, González ME, Márquez J, Matés JM
Biochem J 2005 Mar 15;386(Pt 3):535-42
PMID 15496140
 
Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species
Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y, Sugano S, Sato E, Nagao T, Yokote K, Tatsuno I, Prives C
Proc Natl Acad Sci U S A 2010 Apr 20;107(16):7461-6
PMID 20351271
 
Downregulation of GLS2 in glioblastoma cells is related to DNA hypermethylation but not to the p53 status
Szeliga M, Bogaciñska-Karaś M, Kuźmicz K, Rola R, Albrecht J
Mol Carcinog 2015 Aug 10
PMID 26258493
 
Transfection with liver-type glutaminase cDNA alters gene expression and reduces survival, migration and proliferation of T98G glioma cells
Szeliga M, Obara-Michlewska M, Matyja E, Lazarczyk M, Lobo C, Hilgier W, Alonso FJ, Márquez J, Albrecht J
Glia 2009 Jul;57(9):1014-23
PMID 19062176
 
Lack of expression of the liver-type glutaminase (LGA) mRNA in human malignant gliomas
Szeliga M, Sidoryk M, Matyja E, Kowalczyk P, Albrecht J
Neurosci Lett 2005 Feb 21;374(3):171-3
PMID 15663956
 
Transfection of a human glioblastoma cell line with liver-type glutaminase (LGA) down-regulates the expression of DNA-repair gene MGMT and sensitizes the cells to alkylating agents
Szeliga M, Zgrzywa A, Obara-Michlewska M, Albrecht J
J Neurochem 2012 Nov;123(3):428-36
PMID 22888977
 
Knock-down of glutaminase 2 expression decreases glutathione, NADH, and sensitizes cervical cancer to ionizing radiation
Xiang L, Xie G, Liu C, Zhou J, Chen J, Yu S, Li J, Pang X, Shi H, Liang H
Biochim Biophys Acta 2013 Dec;1833(12):2996-3005
PMID 23954443
 
The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type
Yuneva MO, Fan TW, Allen TD, Higashi RM, Ferraris DV, Tsukamoto T, Matés JM, Alonso FJ, Wang C, Seo Y, Chen X, Bishop JM
Cell Metab 2012 Feb 8;15(2):157-70
PMID 22326218
 

Citation

This paper should be referenced as such :
Campos-Sandoval JA, Martín-Rufián M, Márquez J
GLS2 (Glutaminase 2);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/GLS2ID46328ch12q13.html


External links

Nomenclature
HGNC (Hugo)GLS2   29570
Cards
AtlasGLS2ID46328ch12q13
Entrez_Gene (NCBI)GLS2  27165  glutaminase 2
AliasesGA; GLS; LGA; hLGA
GeneCards (Weizmann)GLS2
Ensembl hg19 (Hinxton)ENSG00000135423 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000135423 [Gene_View]  chr12:56470944-56488414 [Contig_View]  GLS2 [Vega]
ICGC DataPortalENSG00000135423
TCGA cBioPortalGLS2
AceView (NCBI)GLS2
Genatlas (Paris)GLS2
WikiGenes27165
SOURCE (Princeton)GLS2
Genetics Home Reference (NIH)GLS2
Genomic and cartography
GoldenPath hg38 (UCSC)GLS2  -     chr12:56470944-56488414 -  12q13.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)GLS2  -     12q13.3   [Description]    (hg19-Feb_2009)
EnsemblGLS2 - 12q13.3 [CytoView hg19]  GLS2 - 12q13.3 [CytoView hg38]
Mapping of homologs : NCBIGLS2 [Mapview hg19]  GLS2 [Mapview hg38]
OMIM606365   
Gene and transcription
Genbank (Entrez)AF038170 AF110329 AF110330 AF110331 AF223944
RefSeq transcript (Entrez)NM_001280796 NM_001280797 NM_001280798 NM_013267 NM_138566
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)GLS2
Cluster EST : UnigeneHs.212606 [ NCBI ]
CGAP (NCI)Hs.212606
Alternative Splicing GalleryENSG00000135423
Gene ExpressionGLS2 [ NCBI-GEO ]   GLS2 [ EBI - ARRAY_EXPRESS ]   GLS2 [ SEEK ]   GLS2 [ MEM ]
Gene Expression Viewer (FireBrowse)GLS2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)27165
GTEX Portal (Tissue expression)GLS2
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UI32   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9UI32  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UI32
Splice isoforms : SwissVarQ9UI32
Catalytic activity : Enzyme3.5.1.2 [ Enzyme-Expasy ]   3.5.1.23.5.1.2 [ IntEnz-EBI ]   3.5.1.2 [ BRENDA ]   3.5.1.2 [ KEGG ]   
PhosPhoSitePlusQ9UI32
Domaine pattern : Prosite (Expaxy)ANK_REP_REGION (PS50297)    ANK_REPEAT (PS50088)   
Domains : Interpro (EBI)Ankyrin_rpt    Ankyrin_rpt-contain_dom    Beta-lactam/transpept-like    Glutaminase   
Domain families : Pfam (Sanger)Ank_2 (PF12796)    Glutaminase (PF04960)   
Domain families : Pfam (NCBI)pfam12796    pfam04960   
Domain families : Smart (EMBL)ANK (SM00248)  
Conserved Domain (NCBI)GLS2
DMDM Disease mutations27165
Blocks (Seattle)GLS2
PDB (SRS)4BQM   
PDB (PDBSum)4BQM   
PDB (IMB)4BQM   
PDB (RSDB)4BQM   
Structural Biology KnowledgeBase4BQM   
SCOP (Structural Classification of Proteins)4BQM   
CATH (Classification of proteins structures)4BQM   
SuperfamilyQ9UI32
Human Protein AtlasENSG00000135423
Peptide AtlasQ9UI32
HPRD05901
IPIIPI00296219   IPI00142795   IPI00921815   IPI00945631   IPI01009348   IPI00946459   IPI00945998   IPI00877031   
Protein Interaction databases
DIP (DOE-UCLA)Q9UI32
IntAct (EBI)Q9UI32
FunCoupENSG00000135423
BioGRIDGLS2
STRING (EMBL)GLS2
ZODIACGLS2
Ontologies - Pathways
QuickGOQ9UI32
Ontology : AmiGOglutaminase activity  glutaminase activity  protein binding  mitochondrion  mitochondrial matrix  mitochondrial matrix  cellular amino acid metabolic process  glutamate biosynthetic process  glutamine catabolic process  cellular amino acid biosynthetic process  glutamate secretion  regulation of apoptotic process  reactive oxygen species metabolic process  positive regulation of protein targeting to mitochondrion  
Ontology : EGO-EBIglutaminase activity  glutaminase activity  protein binding  mitochondrion  mitochondrial matrix  mitochondrial matrix  cellular amino acid metabolic process  glutamate biosynthetic process  glutamine catabolic process  cellular amino acid biosynthetic process  glutamate secretion  regulation of apoptotic process  reactive oxygen species metabolic process  positive regulation of protein targeting to mitochondrion  
Pathways : KEGG   
REACTOMEQ9UI32 [protein]
REACTOME PathwaysR-HSA-70614 [pathway]   
NDEx NetworkGLS2
Atlas of Cancer Signalling NetworkGLS2
Wikipedia pathwaysGLS2
Orthology - Evolution
OrthoDB27165
GeneTree (enSembl)ENSG00000135423
Phylogenetic Trees/Animal Genes : TreeFamGLS2
HOVERGENQ9UI32
HOGENOMQ9UI32
Homologs : HomoloGeneGLS2
Homology/Alignments : Family Browser (UCSC)GLS2
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerGLS2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)GLS2
dbVarGLS2
ClinVarGLS2
1000_GenomesGLS2 
Exome Variant ServerGLS2
ExAC (Exome Aggregation Consortium)GLS2 (select the gene name)
Genetic variants : HAPMAP27165
Genomic Variants (DGV)GLS2 [DGVbeta]
DECIPHERGLS2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisGLS2 
Mutations
ICGC Data PortalGLS2 
TCGA Data PortalGLS2 
Broad Tumor PortalGLS2
OASIS PortalGLS2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICGLS2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDGLS2
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
LOVD (Leiden Open Variation Database)MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
BioMutasearch GLS2
DgiDB (Drug Gene Interaction Database)GLS2
DoCM (Curated mutations)GLS2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)GLS2 (select a term)
intoGenGLS2
NCG5 (London)GLS2
Cancer3DGLS2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606365   
Orphanet
MedgenGLS2
Genetic Testing Registry GLS2
NextProtQ9UI32 [Medical]
TSGene27165
GENETestsGLS2
Target ValidationGLS2
Huge Navigator GLS2 [HugePedia]
snp3D : Map Gene to Disease27165
BioCentury BCIQGLS2
ClinGenGLS2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD27165
Chemical/Pharm GKB GenePA134933506
Clinical trialGLS2
Miscellaneous
canSAR (ICR)GLS2 (select the gene name)
Probes
Litterature
PubMed42 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineGLS2
EVEXGLS2
GoPubMedGLS2
iHOPGLS2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Jun 7 12:03:44 CEST 2017

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