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| 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). |
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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. |
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. |
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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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