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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

Other aliasCENTG1 (Centaurin , gamma1)
Posphoinositide-3-kinase enhancers (PIKE)-A
AGAP-2
GGAP2
KIAA0167
LocusID (NCBI) 116986
Atlas_Id 44037
Location 12q14.1  [Link to chromosome band 12q14]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
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


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(8;12)(q22;q14) AGAP2/TMEM67


External links

Nomenclature
Cards
AtlasCENTG1ID44037ch12q14.txt
Aliases
Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)116986
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
Miscellaneous
canSAR (ICR) (select the gene name)
Probes
Litterature
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed


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indexed on : Thu Oct 18 17:31:49 CEST 2018

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