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AGAP2 (Centaurin , gamma1)

Written2007-05Chan Chi Bun, Ye Keqiang
Department of Pathology, Laboratory Medicine, Emory University School of Medicine, Atlanta, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesCENTG1
centaurin
HGNC (Hugo) AGAP2
LocusID (NCBI) 116986
Atlas_Id 44037
Location 12q14.1  [Link to chromosome band 12q14]
Location_base_pair Starts at 58118076 and ends at 58132029 bp from pter ( according to hg19-Feb_2009)  [Mapping AGAP2.png]
Fusion genes
(updated 2016)
AGAP2 (12q14.1) / IL11 (19q13.42)AGAP2 (12q14.1) / TMEM67 (8q22.1)BUD31 (7q22.1) / AGAP2 (12q14.1)
ZNF740 (12q13.13) / AGAP2 (12q14.1)

DNA/RNA

 
  Schematic diagram of the CENTG1 gene. The exon numbers are labeled.
Description CENTG1 gene, located on reverse strand, comprises of 18439 bp, which consists of 20 exons and 19 introns.
Transcription Transcription of CENTG1 takes place in a telomeric to centromere orientation. Two isoforms, namely PIKE-L (3579) and PIKE-A (3938 bp) were identified. No systematic investigations on the production of the two isoforms have been reported but it is suggested that they were produced through alternative splicing and utilization of transcription initiation site. Transcription of PIKE-L begins at exon 2 through 20. Transcription of PIKE-A utilizes another initiation site which begins at exon 1 through 20. Moreover, exon 15 is skipped during the transcription of PIKE-A.
Pseudogene No pseudogene of CENTG1 has been reported.

Protein

 
  Schematic diagram of PIKE-A protein. PIKE-A contains a GTPase domain, a pleckstrin homology (PH) domain, an ADP ribosylation factor-GTPase activating protein (Arf-GAP) domain and ankyrin repeats (ANK).
Description PIKE-A proteins contains 836 amino acids (about 91kDa). It possesses a GTPase domain (aminoacids 143-300), a pleckstrin homology (PH) domain (aminoacids 343-552), an ADP ribosylation factor3 GTPase Activating Protein (Arf-GAP) domain (aminoacids 577-695) and ankyrin repeats (ANK) (aminoacids 702-291). PIKE-A could be cleaved at Asp474 and Asp592 during apoptosis. However, phosphorylation of PIKE-A by Fyn at Tyr682 and Tyr774 protects this apoptotic cleavage.
Expression PIKE-A mRNA is ubiquitously expressed. Northern blot analysis revealed that the highest expression was found in brain (cerebellum, cerebral cortex, occipital pole, frontal lobe, temporal lobe and putamen) followed by spleen, thymus and periphery blood leukocytes. Detectable amount of PIKE-A mRNA could be found in lung, liver, and small intestine. No signal was detected in heart, placenta, kidney, prostate gland, pancreas, testis, ovary and colon.
Localisation PIKE-A localizes in both the cytoplasm and the nucleus in COS-7, NIH3T3 and CRL-2061 sarcoma cells. In HEK293 cells, PIKE-A exclusively locates in the cytoplasm. Within the NIH3T3 nucleus, PIKE-A resides in the nucleolus.
Function PIKE-A is a GTPase that catalyze the bound GTP to GDP. Its intrinsic GTPase activity is regulated by its C-terminal Arf-GAP domain and PI(3,4,5)P3. In the studies aiming at determining the GTPase activity of various PIKE-A domain in vitro, it was found that the GTPase activity of PIKE-A was dampened when the Arf-GAP domain was absence. Further studies revealed that full-length PIKE-A possessed negligible GTPase activity in the absence of phosphatidylinositol lipid which could be enhanced in the presence of PI(3,4,5)P3. It is suggested that phosphatidylinositol lipids may regulate PIKE-A conformation through its PH domain, leading to the C-terminal Arf-GAP domain accessible to its GTPase domain and accelerating its intrinsic GTPase activity.

PIKE-A is also a physiological interacting partner of protein kinase B (Akt). It was reported that PIKE-A specifically interacted with the regulatory domain and partial catalytic domain of activated Akt thorough its GTPase domain. Moreover, this interaction was guanine nucleotide dependent as the presence of GTPgammaS strongly stimulated their binding. Through interacting with PIKE-A, both basal and growth factor (e.g. EGF) stimulated Akt activity is greatly enhanced. This enhanced Akt activity is not triggered by uplifting PI3-kinase activity as PIKE-A neither interacts with PI3-kinase nor affects its activity. Instead, PIKE-A maintains and initiates Akt activation directly in both U87MG and LN-Z308 cells.

Overexpression of PIKE-A in U87MG glioblastoma cells promotes cell proliferation and enhances its invasion activity by stimulating Akt activity. In contrast, depletion of PIKE-A decreases U87MG viability upon staurosporine treatment via enhancing apoptosis.

Homology PIKE-A is a member of gamma subfamily of centaurin GTPase superfamily, which consists of alpha, beta, gamma, and dela subfamilies. Centaurin gamma subfamily has three members which are gamma1 (PIKE-A), gamma2 (CENTG2) and gama3 (CENTG3). PIKE-A shares only about 56% and 47% amino acid identity with CENTG2 and CENTG3.

Mutations

Germinal No germinal mutation of CENTG1 has been reported.
Somatic PIKE-A mutation was observed in bone sarcoma CRL2098 (R182G, V591M and deletion of aa 756-777), neuroblastoma NGP-127 (T232I), glioblastomas M067 (V119A, S666P) and SF188 (A315V, L360E, E431V and N583D). These mutations altered the GTP binding, GTPase activity and cellular localization of PIKE-A. PIKE-A mutant from NGP-127 hydrolyzed GTP into GDP more potently than those from CRL2098, M067 and SF188. On the other hand, GTP binding to PIKE-A is more profound in CRL2098, M067, SF188 mutant than NGP-127 mutant. All PIKE-A mutants showed similar cytoplasmic localization patternin HEK293 cells under basal condition. However, when the cells were stimulated with EGF, those mutants from CRL2098, M067 and NGP-127 aggregated in perinuclear zone. No such aggregation was detected in mutants from SF188 cells. Furthermore, cellular morphological transformation from regular round shape to spindle-shaped refractile morphology was observed in NIH3T3 cells transfected with PIKE-A mutants derived from M067 and SF188 cells.

Implicated in

Note
Entity Glioblastoma
Cytogenetics Chromosome 12q13-q15 is frequently amplified in brain tumors. This chromosomal region contains the MDM2, CDK2 and CENTG1 gene. Subsequent studies revealed CENTG1 was substantially amplified in glioblastoma cell line TP366, LN-Z308 and CRL-2061 genome in addition to a normal CENTG1 on chromosome 12. Further, PIKE-A is markedly amplified as double-minute chromatin bodies in SF-188. This amplification occurs in about 16.7% of primary glioblastoma and 11.1% of glioblastoma cell lines.
Oncogenesis In addition to overexpression in glioblastoma TP366, LN-Z308, CRL2061 and SF188 cells, mutation of PIKE-A is observed in M067 and SF188 glioblastoma. Studies using nontransforming NIH3T3 cells revealed that overexpression of these PIKE-A mutants strongly promoted cell proliferation in an anchorage-independent manner possibly through enhanced Akt activity. In U87MG glioblastoma, which has low PIKE-A expression, overexpression of PIKE-A mutants derived from M067 and SF188 greatly enhanced Akt and ERK phosphorylation, thereby enhancing cell proliferation and invasion, and preventing apoptotic cell death.
  

To be noted

PIKE-A is overexpressed in human cancers derived from a great variety of tissues including breast, ovary, colon, stomach, lung, kidney, bladder, vulva, uterus, cervix, rectum, testis and skin.

Bibliography

PIKE-A is amplified in human cancers and prevents apoptosis by up-regulating Akt.
Ahn JY, Hu Y, Kroll TG, Allard P, Ye K
Proceedings of the National Academy of Sciences of the United States of America. 2004 ; 101 (18) : 6993-6998.
PMID 15118108
 
PIKE (phosphatidylinositol 3-kinase enhancer)-A GTPase stimulates Akt activity and mediates cellular invasion.
Ahn JY, Rong R, Kroll TG, Van Meir EG, Snyder SH, Ye K
The Journal of biological chemistry. 2004 ; 279 (16) : 16441-16451.
PMID 14761976
 
Transcript mapping in a 46-kb sequenced region at the core of 12q13.3 amplification in human cancers.
Elkahloun AG, Krizman DB, Wang Z, Hofmann TA, Roe B, Meltzer PS
Genomics. 1997 ; 42 (2) : 295-301.
PMID 9192850
 
Phosphoinositol lipids bind to phosphatidylinositol 3 (PI3)-kinase enhancer GTPase and mediate its stimulatory effect on PI3-kinase and Akt signalings.
Hu Y, Liu Z, Ye K
Proceedings of the National Academy of Sciences of the United States of America. 2005 ; 102 (46) : 16853-16858.
PMID 16263930
 
Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas.
Knobbe CB, Trampe-Kieslich A, Reifenberger G
Neuropathology and applied neurobiology. 2005 ; 31 (5) : 486-490.
PMID 16150119
 
PIKE-A is a proto-oncogene promoting cell growth, transformation and invasion.
Liu X, Hu Y, Hao C, Rempel SA, Ye K
Oncogene. 2007 ; 26 (34) : 4918-4927.
PMID 17297440
 
Prediction of the coding sequences of unidentified human genes. V. The coding sequences of 40 new genes (KIAA0161-KIAA0200) deduced by analysis of cDNA clones from human cell line KG-1.
Nagase T, Seki N, Ishikawa K, Tanaka A, Nomura N
DNA research : an international journal for rapid publication of reports on genes and genomes. 1996 ; 3 (1) : 17-24.
PMID 8724849
 
Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival.
Tang X, Feng Y, Ye K
Cell death and differentiation. 2007 ; 14 (2) : 368-377.
PMID 16841086
 
Pike tyrosine phosphorylation regulates its apoptotic cleavage during programmed cell death.
Tang X, Ye K
Advances in enzyme regulation. 2006 ; 46 : 289-300.
PMID 16854451
 
GGAPs, a new family of bifunctional GTP-binding and GTPase-activating proteins.
Xia C, Ma W, Stafford LJ, Liu C, Gong L, Martin JF, Liu M
Molecular and cellular biology. 2003 ; 23 (7) : 2476-2488.
PMID 12640130
 

Citation

This paper should be referenced as such :
Chi Bun, Chan ; Keqiang, Ye
CENTG1 (Centaurin , gamma1)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4):297-299.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CENTG1ID44037ch12q14.html


External links

Nomenclature
HGNC (Hugo)AGAP2   16921
Cards
AtlasCENTG1ID44037ch12q14
Entrez_Gene (NCBI)AGAP2  116986  ArfGAP with GTPase domain, ankyrin repeat and PH domain 2
AliasesCENTG1; GGAP2; PIKE
GeneCards (Weizmann)AGAP2
Ensembl hg19 (Hinxton)ENSG00000135439 [Gene_View]  chr12:58118076-58132029 [Contig_View]  AGAP2 [Vega]
Ensembl hg38 (Hinxton)ENSG00000135439 [Gene_View]  chr12:58118076-58132029 [Contig_View]  AGAP2 [Vega]
ICGC DataPortalENSG00000135439
TCGA cBioPortalAGAP2
AceView (NCBI)AGAP2
Genatlas (Paris)AGAP2
WikiGenes116986
SOURCE (Princeton)AGAP2
Genetics Home Reference (NIH)AGAP2
Genomic and cartography
GoldenPath hg19 (UCSC)AGAP2  -     chr12:58118076-58132029 -  12q13.2   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)AGAP2  -     12q13.2   [Description]    (hg38-Dec_2013)
EnsemblAGAP2 - 12q13.2 [CytoView hg19]  AGAP2 - 12q13.2 [CytoView hg38]
Mapping of homologs : NCBIAGAP2 [Mapview hg19]  AGAP2 [Mapview hg38]
OMIM605476   
Gene and transcription
Genbank (Entrez)AF384128 AF413077 AK122827 AK292672 AV740795
RefSeq transcript (Entrez)NM_001122772 NM_014770
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)AGAP2
Cluster EST : UnigeneHs.302435 [ NCBI ]
CGAP (NCI)Hs.302435
Alternative Splicing GalleryENSG00000135439
Gene ExpressionAGAP2 [ NCBI-GEO ]   AGAP2 [ EBI - ARRAY_EXPRESS ]   AGAP2 [ SEEK ]   AGAP2 [ MEM ]
Gene Expression Viewer (FireBrowse)AGAP2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)116986
GTEX Portal (Tissue expression)AGAP2
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ99490   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ99490  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ99490
Splice isoforms : SwissVarQ99490
PhosPhoSitePlusQ99490
Domaine pattern : Prosite (Expaxy)ANK_REP_REGION (PS50297)    ANK_REPEAT (PS50088)    ARFGAP (PS50115)    PH_DOMAIN (PS50003)    RAB (PS51419)   
Domains : Interpro (EBI)Ankyrin_rpt    Ankyrin_rpt-contain_dom    ArfGAP    P-loop_NTPase    PH_dom-like    PH_domain    Small_GTPase   
Domain families : Pfam (Sanger)Ank_2 (PF12796)    ArfGap (PF01412)    Ras (PF00071)   
Domain families : Pfam (NCBI)pfam12796    pfam01412    pfam00071   
Domain families : Smart (EMBL)ArfGap (SM00105)  PH (SM00233)  
Conserved Domain (NCBI)AGAP2
DMDM Disease mutations116986
Blocks (Seattle)AGAP2
PDB (SRS)2BMJ    2IWR    2RLO   
PDB (PDBSum)2BMJ    2IWR    2RLO   
PDB (IMB)2BMJ    2IWR    2RLO   
PDB (RSDB)2BMJ    2IWR    2RLO   
Structural Biology KnowledgeBase2BMJ    2IWR    2RLO   
SCOP (Structural Classification of Proteins)2BMJ    2IWR    2RLO   
CATH (Classification of proteins structures)2BMJ    2IWR    2RLO   
SuperfamilyQ99490
Human Protein AtlasENSG00000135439
Peptide AtlasQ99490
HPRD05687
IPIIPI00217393   IPI00015401   IPI01021041   IPI01021198   IPI00884044   
Protein Interaction databases
DIP (DOE-UCLA)Q99490
IntAct (EBI)Q99490
FunCoupENSG00000135439
BioGRIDAGAP2
STRING (EMBL)AGAP2
ZODIACAGAP2
Ontologies - Pathways
QuickGOQ99490
Ontology : AmiGOGTPase activator activity  protein binding  GTP binding  nucleus  nucleus  nucleolus  mitochondrion  small GTPase mediated signal transduction  protein transport  membrane  negative regulation of protein catabolic process  negative regulation of neuron apoptotic process  positive regulation of GTPase activity  metal ion binding  extracellular exosome  
Ontology : EGO-EBIGTPase activator activity  protein binding  GTP binding  nucleus  nucleus  nucleolus  mitochondrion  small GTPase mediated signal transduction  protein transport  membrane  negative regulation of protein catabolic process  negative regulation of neuron apoptotic process  positive regulation of GTPase activity  metal ion binding  extracellular exosome  
Pathways : KEGGFoxO signaling pathway    Endocytosis   
REACTOMEQ99490 [protein]
REACTOME PathwaysR-HSA-373752 [pathway]
NDEx NetworkAGAP2
Atlas of Cancer Signalling NetworkAGAP2
Wikipedia pathwaysAGAP2
Orthology - Evolution
OrthoDB116986
GeneTree (enSembl)ENSG00000135439
Phylogenetic Trees/Animal Genes : TreeFamAGAP2
HOVERGENQ99490
HOGENOMQ99490
Homologs : HomoloGeneAGAP2
Homology/Alignments : Family Browser (UCSC)AGAP2
Gene fusions - Rearrangements
Fusion : MitelmanAGAP2/TMEM67 [12q14.1/8q22.1]  
Fusion: TCGAAGAP2 12q14.1 TMEM67 8q22.1 GBM
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerAGAP2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)AGAP2
dbVarAGAP2
ClinVarAGAP2
1000_GenomesAGAP2 
Exome Variant ServerAGAP2
ExAC (Exome Aggregation Consortium)AGAP2 (select the gene name)
Genetic variants : HAPMAP116986
Genomic Variants (DGV)AGAP2 [DGVbeta]
DECIPHER (Syndromes)12:58118076-58132029  ENSG00000135439
CONAN: Copy Number AnalysisAGAP2 
Mutations
ICGC Data PortalAGAP2 
TCGA Data PortalAGAP2 
Broad Tumor PortalAGAP2
OASIS PortalAGAP2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICAGAP2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDAGAP2
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 AGAP2
DgiDB (Drug Gene Interaction Database)AGAP2
DoCM (Curated mutations)AGAP2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)AGAP2 (select a term)
intoGenAGAP2
NCG5 (London)AGAP2
Cancer3DAGAP2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM605476   
Orphanet
MedgenAGAP2
Genetic Testing Registry AGAP2
NextProtQ99490 [Medical]
TSGene116986
GENETestsAGAP2
Huge Navigator AGAP2 [HugePedia]
snp3D : Map Gene to Disease116986
BioCentury BCIQAGAP2
ClinGenAGAP2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD116986
Chemical/Pharm GKB GenePA26411
Clinical trialAGAP2
Miscellaneous
canSAR (ICR)AGAP2 (select the gene name)
Probes
Litterature
PubMed49 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineAGAP2
EVEXAGAP2
GoPubMedAGAP2
iHOPAGAP2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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