Review on CENTG1 (Centaurin , gamma1), with data on DNA, on the protein encoded, and where the gene is implicated

Chi Bun, Chan

Keqiang, Ye

Atlas of Genetics and Cytogenetics in Oncology and Haematology

I-Revues

  
 
 
 
 
Gene Section 
Mini Review 
 
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4)  297 
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology                         
                         OPEN ACCESS JOURNAL AT INIST-CNRS 
CENTG1 (centaurin, gamma1) 
Chan Chi Bun, Ye Keqiang 
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, USA 
Published in Atlas Database: May 2007 
Online updated version: http://AtlasGeneticsOncology.org/Genes/CENTG1ID44037ch12q14.html  
DOI: 10.4267/2042/16962 
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. 
© 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
 
Identity 
Hugo: CENTG1 
Other names: Posphoinositide-3-kinase enhancers 
(PIKE)-A; AGAP-2; GGAP2; KIAA0167 
Location: 12q14.1 
DNA/RNA 
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. 
 
 
Schematic diagram of the CENTG1 gene. The exon numbers are labeled. 
 
 
 
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). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CENTG1 (centaurin, gamma1) Chi Bun C, Keqiang Y 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4)  298 
Protein 
Description 
PIKE-A proteins contains 836 amino acids (about 91 
kDa). 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 
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 
CENTG1 (centaurin, gamma1) Chi Bun C, Keqiang Y 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4)  299 
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 
Note: 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. 
References 
Nagase T, Seki N, Ishikawa K, Tanaka A, Nomura N. 
Prediction of the coding sequences of 40 new genes 
(KIAA0161-KIAA0200) deduced by analysis of cDNA clones 
from human cell line KG-1. DNA Res 1996;3:17-24. 
Elkahloun AG, Krizman DB, Wang Z, Hofmann TA, Roe B, 
Meltzer PS. Transcript mapping in a 46-kb sequenced region 
at the core of 12q13.3 amplification in human cancers. 
Genomics 1997;42:295-301. 
Xia C, Ma W, Stafford LJ, Liu C, Gong L, Martin JF, Liu M. 
GGAPs, a new family of bifunctional GTP-binding and 
GTPase-activating proteins. Mol Cell Biol 2003;23:2476-2488. 
Ahn JY, Hu Y, Kroll TG, Allard P, Ye K. PIKE-A is amplified in 
human cancers and prevents apoptosis by up-regulating Akt. 
Proc Natl Acad Sci USA 2004;101:6993-6998. 
Ahn JY, Rong R, Kroll TG, Van Meir EG, Snyder SH, Ye K. 
PIKE (phosphatidylinositol 3-kinase enhancer)-A GTPase 
stimulates Akt activity and mediates cellular invasion. J Biol 
Chem 2004;279:16441-16451. 
Hu Y, Liu Z, Ye K. Phosphoinositol lipids bind to 
phosphatidylinositol 3 (PI3)-kinase enhancer GTPase and 
mediates its stimulatory effect on PI3-kinase and Akt 
signalings. Proc Natl Acad Sci USA 2005;102:16853-16858. 
Knobbe CB, Trampe-Kieslich A, Reifenberger G. Genetic 
alteration and expression of the phosphoinositol-3-kinase/Akt 
pathway genes PIK3CA and PIKE in human glioblastomas. 
Neuropath Appl Neurobiol 2005;31:486-490. 
Tang X, Feng Y, Ye K. Src-family tyrosine kinase Fyn 
phosphrylates phosphatidylinositol 3-kinase enhancer 
activating Akt, preventing its apoptotic cleavage and promoting 
cell survival. Cell Death Differ 2006;14:368-377. 
Tang X, Ye K. PIKE tyrosine phosphorylation regulates its 
apoptotic cleavage during programmed cell death. Advan 
Enzyme Regul 2006;46:289-300. 
Liu X, Hu Y, Hao C, Rempel SA, Ye K. PIKE-A is a proto-
oncogene promoting cell growth, transformation and invasion. 
Oncogene 2007;in press. 
This article should be referenced as such: 
Chi Bun C, Keqiang Y. CENTG1 (centaurin, gamma1). Atlas 
Genet Cytogenet Oncol Haematol.2007;11(4):297-299.  
 
 


CENTG1 (Centaurin , gamma1)

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CENTG1 (Centaurin , gamma1)

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