G2Cdb::Gene report

Gene id
Gene symbol
Homo sapiens
ArfGAP with GTPase domain, ankyrin repeat and PH domain 2
G00000023 (Mus musculus)

Databases (7)

ENSG00000135439 (Ensembl human gene)
116986 (Entrez Gene)
563 (G2Cdb plasticity & disease)
CENTG1 (GeneCards)
605476 (OMIM)
Marker Symbol
HGNC:16921 (HGNC)
Protein Sequence
Q99490 (UniProt)

Literature (28)

Pubmed - other

  • Arf GTPase-activating protein AGAP2 regulates focal adhesion kinase activity and focal adhesion remodeling.

    Zhu Y, Wu Y, Kim JI, Wang Z, Daaka Y and Nie Z

    Department of Pathology, Medical College of Georgia, Augusta, Georgia 30912, USA.

    Focal adhesions are specialized sites of cell attachment to the extracellular matrix where integrin receptors link extracellular matrix to the actin cytoskeleton, and they are constantly remodeled during cell migration. Focal adhesion kinase (FAK) is an important regulator of focal adhesion remodeling. AGAP2 is an Arf GTPase-activating protein that regulates endosomal trafficking and is overexpressed in different human cancers. Here we examined the regulation of the FAK activity and the focal adhesion remodeling by AGAP2. Our results show that FAK binds the pleckstrin homology domain of AGAP2, and the binding is independent of FAK activation following epidermal growth factor receptor stimulation. Overexpression of AGAP2 augments the activity of FAK, and concordantly, the knockdown of AGAP2 expression with RNA interference attenuates the FAK activity stimulated by epidermal growth factor or platelet-derived growth factor receptors. AGAP2 is localized to the focal adhesions, and its overexpression results in dissolution of the focal adhesions, whereas knockdown of its expression stabilizes them. The AGAP2-induced dissolution of the focal adhesions is independent of its GTPase-activating protein activity but may involve its N-terminal G protein-like domain. Our results indicate that AGAP2 regulates the FAK activity and the focal adhesion disassembly during cell migration.

    Funded by: NCI NIH HHS: CA129155, CA131988

    The Journal of biological chemistry 2009;284;20;13489-96

  • GGAP2/PIKE-a directly activates both the Akt and nuclear factor-kappaB pathways and promotes prostate cancer progression.

    Cai Y, Wang J, Li R, Ayala G, Ittmann M and Liu M

    Department of Pathology, Baylor College of Medicine, Texas A&M University System Health Science Center, Houston, Texas 77030, USA.

    GGAP2/PIKE-A is a GTP-binding protein that can enhance Akt activity. Increased activation of the AKT and nuclear factor-kappaB (NF-kappaB) pathways have been identified as critical steps in cancer initiation and progression in a variety of human cancers. We have found significantly increased expression GGAP2 in the majority of human prostate cancers and GGAP2 expression increases Akt activation in prostate cancer cells. Thus, increased GGAP2 expression is a common mechanism for enhancing the activity of the Akt pathway in prostate cancers. In addition, we have found that activated Akt can bind and phosphorylate GGAP2 at serine 629, which enhances GTP binding by GGAP2. Phosphorylated GGAP2 can bind the p50 subunit of NF-kappaB and enhances NF-kappaB transcriptional activity. When expressed in prostate cancer cells, GGAP2 enhances proliferation, foci formation, and tumor progression in vivo. Thus, increased GGAP2 expression, which is present in three quarters of human prostate cancers, can activate two critical pathways that have been linked to prostate cancer initiation and progression.

    Funded by: NCI NIH HHS: 1R01CA106479, P50 CA058204, R01 CA106479, R01 CA106479-04

    Cancer research 2009;69;3;819-27

  • Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B.

    Tang X, Jang SW, Okada M, Chan CB, Feng Y, Liu Y, Luo SW, Hong Y, Rama N, Xiong WC, Mehlen P and Ye K

    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

    Netrins, a family of secreted molecules, have critical functions in axon guidance and cell migration during neuronal development. In addition to its role as a chemotropic molecule, netrin-1 also acts as a survival factor. Both UNC5 (that is, UNC5A, UNC5B, UNC5C or UNC5D) and DCC are transmembrane receptors for netrin-1 (Refs 8, 9). In the absence of netrin-1, DCC and UNC5 act as dependence receptors and trigger apoptosis. However, how netrin-1 suppresses the apoptotic activity of the receptors remains elusive. Here we show that netrin-1 induces interaction of UNC5B with the brain-specific GTPase PIKE-L. This interaction triggers the activation of PtdIns-3-OH kinase signalling, prevents UNC5B's pro-apoptotic activity and enhances neuronal survival. Moreover, this process relies strongly on Fyn because PIKE-L is tyrosine phosphorylated in response to netrin-1, and the netrin-1-mediated interaction of UNC5B with PIKE-L is inhibited in Fyn-null mice. Thus, PIKE-L acts as a downstream survival effector for netrin-1 through UNC5B in the nervous system.

    Funded by: NINDS NIH HHS: R01 NS045627, R01 NS045627-05

    Nature cell biology 2008;10;6;698-706

  • Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion.

    Liu R, Tian B, Gearing M, Hunter S, Ye K and Mao Z

    Departments of Pharmacology, Neurology, and Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.

    Isoform A of phosphatidylinositol 3-kinase enhancer (PIKE-A) is a newly identified prooncogenic factor that has been implicated in cancer cell growth. How PIKE-A activity is regulated in response to growth signal is poorly understood. Here, we demonstrate that cyclin dependent kinase 5 (Cdk5), a protein known to function mainly in postmitotic neurons, directly phosphorylates PIKE-A at Ser-279 in its GTPase domain in glioblastoma cells. This phosphorylation event stimulates PIKE-A GTPase activity and the activity of its downstream effector Akt. Growth signal activates Cdk5 and results in a Cdk5-dependent accumulation of phosphorylated PIKE-A and activation of Akt in the nucleus. Furthermore, PIKE-A phosphorylation and Cdk5 are increased in human glioblastoma specimens. Phosphorylation of PIKE-A by Cdk5 mediates growth factor-induced migration and invasion of human glioblastoma cells. Together, these findings identify PIKE as the first Cdk5 target in cancer cells, revealing a previously undescribed regulatory mechanism that mediates growth signal-induced activation of PIKE-A/Akt and tumor invasion.

    Funded by: NIA NIH HHS: AG023695, R01 AG023695; NINDS NIH HHS: R01 NS048254

    Proceedings of the National Academy of Sciences of the United States of America 2008;105;21;7570-5

  • Split pleckstrin homology domain-mediated cytoplasmic-nuclear localization of PI3-kinase enhancer GTPase.

    Yan J, Wen W, Chan LN and Zhang M

    Department of Biochemistry, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, PR China.

    Cytoplasm-nucleus shuttling of phosphoinositol 3-kinase enhancer (PIKE) is known to correlate directly with its cellular functions. However, the molecular mechanism governing this shuttling is not known. In this work, we demonstrate that PIKE is a new member of split pleckstrin homology (PH) domain-containing proteins. The structure solved in this work reveals that the PIKE PH domain is split into halves by a positively charged nuclear localization sequence. The PIKE PH domain binds to the head groups of di- and triphosphoinositides with similar affinities. Lipid membrane binding of the PIKE PH domain is further enhanced by the positively charged nuclear localization sequence, which is juxtaposed to the phosphoinositide head group-binding pocket of the domain. We demonstrate that the cytoplasmic-nuclear shuttling of PIKE is dynamically regulated by the balancing actions of the lipid-binding property of both the split PH domain and the nuclear targeting function of its nuclear localization sequence.

    Journal of molecular biology 2008;378;2;425-35

  • Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase.

    Liu Z, Jang SW, Liu X, Cheng D, Peng J, Yepes M, Li XJ, Matthews S, Watts C, Asano M, Hara-Nishimura I, Luo HR and Ye K

    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.

    Ischemia and seizure cause excessive neuronal excitation that is associated with brain acidosis and neuronal cell death. However, the molecular mechanism of acidification-triggered neuronal injury is incompletely understood. Here, we show that asparagine endopeptidase (AEP) is activated under acidic condition, cuts SET, an inhibitor of DNase, and triggers DNA damage in brain, which is inhibited by PIKE-L. SET, a substrate of caspases, was cleaved by acidic cytosolic extract independent of caspase activation. Fractionation of the acidic cellular extract yielded AEP that is required for SET cleavage. We found that kainate provoked AEP activation and SET cleavage at N175, triggering DNA nicking in wild-type, but not AEP null, mice. PIKE-L strongly bound SET and prevented its degradation by AEP, leading to resistance of neuronal cell death. Moreover, AEP also mediated stroke-provoked SET cleavage and cell death in brain. Thus, AEP might be one of the proteinases activated by acidosis triggering neuronal injury during neuroexcitotoxicity or ischemia.

    Funded by: NINDS NIH HHS: NS-49478, R01 NS045627, R01 NS045627-05, R01 NS049478

    Molecular cell 2008;29;6;665-78

  • Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation.

    Tang X, Jang SW, Wang X, Liu Z, Bahr SM, Sun SY, Brat D, Gutmann DH and Ye K

    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.

    The neurofibromatosis-2 (NF2) tumour-suppressor gene encodes an intracellular membrane-associated protein, called merlin, whose growth-suppressive function is dependent on its ability to form interactions through its intramolecular amino-terminal domain (NTD) and carboxy-terminal domain (CTD). Merlin phosphorylation plays a critical part in dictating merlin NTD/CTD interactions as well as in controlling binding to its effector proteins. Merlin is partially regulated by phosphorylation of Ser 518, such that hyperphosphorylated merlin is inactive and fails to form productive intramolecular and intermolecular interactions. Here, we show that the protein kinase Akt directly binds to and phosphorylates merlin on residues Thr 230 and Ser 315, which abolishes merlin NTD/CTD interactions and binding to merlin's effector protein PIKE-L and other binding partners. Furthermore, Akt-mediated phosphorylation leads to merlin degradation by ubiquitination. These studies demonstrate that Akt-mediated merlin phosphorylation regulates the function of merlin in the absence of an inactivating mutation.

    Funded by: NCI NIH HHS: R01 (CA117872)

    Nature cell biology 2007;9;10;1199-207

  • PIKE-A is a proto-oncogene promoting cell growth, transformation and invasion.

    Liu X, Hu Y, Hao C, Rempel SA and Ye K

    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

    PIKE-A (phosphoinositide 3-kinases (PI 3)-kinase enhancer) is a ubiquitously expressed GTPase, which binds to and enhances protein kinase B (Akt) kinase activity in a guanine nucleotide-dependent manner. PIKE-A is one of the components of the CDK4 amplicon that is amplified in numerous human cancers. However, whether PIKE-A itself can mediate cell transformation, proliferation and migration remains unknown. Here, we show that PIKE-A is overexpressed in various human cancer samples, escalates U87MG glioblastoma invasion and provokes NIH3T3 cell transformation. Overexpression of wild-type (WT) PIKE-A enhances NIH3T3 and U87MG cell growth, which is further increased by cancer cell-derived PIKE-A active mutants. In contrast, both the dominant-negative mutant and the phosphoinositide lipids interaction-defective mutant antagonize cell proliferation. Moreover, PIKE-A and its active and inactive mutants similarly enhance or antagonize U87MG cell survival and invasion, and their ability to do so is coupled with the catalytic effect they have on Akt activation. Furthermore, PIKE-A WT and its active mutants significantly elicit NIH3T3 cell transformation. Thus, our findings support the concept that PIKE-A acts as a proto-oncogene, promoting cell transformation through Akt activation.

    Funded by: NINDS NIH HHS: R01 NS045627

    Oncogene 2007;26;34;4918-27

  • Nuclear functions of the Arf guanine nucleotide exchange factor BRAG2.

    Dunphy JL, Ye K and Casanova JE

    Department of Cell Biology, University of Virginia Health Sciences Center, Box 800732, Charlottesville, VA 22908, USA.

    BRAG2 is a guanine nucleotide exchange factor for the GTPase Arf6 that cycles between the cytoplasm and nucleus in a CRM1/exportin1-dependent manner. Despite its presence in the nucleus, nuclear functions have not previously been described. Here, we show that depletion of endogenous BRAG2 by RNAi leads to an increased number of Cajal bodies (CBs), and altered structure of nucleoli, as indicated by less focal fibrillarin staining. This result was surprising given that nuclear BRAG2 is diffusely distributed throughout the nucleoplasm and is not concentrated within nucleoli at steady state. However, we found that ectopic expression of the nuclear GTPase PIKE/AGAP2 causes both BRAG2 and the CB marker coilin to accumulate in nucleoli. Neither the GTPase activity of PIKE nor the nucleotide exchange activity of BRAG2 is required for this nucleolar concentration. Increased levels of exogenous BRAG2 in nucleoli result in a redistribution of fibrillarin to the nucleolar periphery, supporting a role for BRAG2 in regulating nucleolar architecture. These observations suggest that, in addition to its role in endocytic regulation at the plasma membrane, BRAG2 also functions within the nucleus.

    Traffic (Copenhagen, Denmark) 2007;8;6;661-72

  • M-T5, the ankyrin repeat, host range protein of myxoma virus, activates Akt and can be functionally replaced by cellular PIKE-A.

    Werden SJ, Barrett JW, Wang G, Stanford MM and McFadden G

    Department of Microbiology and Immunology, University of Western Ontario and Robarts Research Institute, London, Ontario, Canada.

    The myxoma virus (MV) ankyrin repeat, host range factor M-T5 has the ability to bind and activate cellular Akt, leading to permissive MV replication in a variety of diverse human cancer cell lines (G. Wang, J. W. Barrett, M. Stanford, S. J. Werden, J. B. Johnston, X. Gao, M. Sun, J. Q. Cheng, and G. McFadden, Proc. Natl. Acad. Sci. USA 103:4640-4645, 2006). The susceptibility of permissive human cancer cells to MV infection is directly correlated with the basal or induced levels of phosphorylated Akt. When M-T5 is deleted from MV, the knockout virus, vMyxT5KO, can no longer productively infect a subset of human cancer cells (designated type II) that exhibit little or no endogenous phosphorylated Akt. In searching for a host counterpart of M-T5, we noted sequence similarity of M-T5 to a recently identified ankyrin repeat cellular binding protein of Akt called PIKE-A. PIKE-A binds and activates the kinase activity of Akt in a GTP-dependent manner and promotes the invasiveness of human cancer cell lines. Here, we demonstrate that transfected PIKE-A is able to rescue the ability of vMyxT5KO to productively infect type II human cancer cells that were previously resistant to infection. Also, cancer cells that were completely nonpermissive for both wild-type and vMyxT5KO infection (called type III) were rendered fully permissive following ectopic expression of PIKE-A. We conclude that the MV M-T5 host range protein is functionally interchangeable with the host PIKE-A protein and that the activation of host Akt by either M-T5 or PIKE-A is critical for the permissiveness of human cancer cells for MV.

    Journal of virology 2007;81;5;2340-8

  • The centaurin gamma-1 GTPase-like domain functions as an NTPase.

    Soundararajan M, Yang X, Elkins JM, Sobott F and Doyle DA

    The Structural Genomics Consortium, University of Oxford, Botnar Research Centre, Oxford OX3 7LD, UK.

    Centaurins are a family of proteins that contain GTPase-activating protein domains, with the gamma family members containing in addition a GTPase-like domain. Centaurins reside mainly in the nucleus and are known to activate phosphoinositide 3-kinase, a key regulator of cell proliferation, motility and vesicular trafficking. In the present study, using X-ray structural analysis, enzymatic assays and nucleotide-binding studies, we show that, for CENTG1 (centaurin gamma-1) the GTPase-like domain has broader trinucleotide specificity. Alterations within the G4 motif of CENTG1 from the highly conserved NKXD found in typical GTPases to TQDR result in the loss of specificity, a lower affinity for the nucleotides and higher turnover rates. These results indicate that the centaurins could be more accurately classified as NTPases and point to alternative mechanisms of cell signalling control.

    Funded by: Wellcome Trust

    The Biochemical journal 2007;401;3;679-88

  • Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival.

    Tang X, Feng Y and Ye K

    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Room 145, Whitehead Building, 615 Michael Street, Atlanta, GA 30322, USA.

    Phosphatidylinositol 3-kinase enhancer-activating Akt (PIKE-A) binds Akt and upregulates its kinase activity, preventing apoptosis. PIKE-A can be potently phosphorylated on tyrosine residues 682 and 774, leading to its resistance to caspase cleavage. However, the upstream tyrosine kinases responsible for PIKE-A phosphorylation and subsequent physiological significance remain unknown. Here, we show that PIKE-A can be cleaved by the active apoptosome at both D474 and D592 residues. Employing fyn-deficient mouse embryonic fibroblast cells and tissues, we demonstrate that fyn is essential for phosphorylating PIKE-A and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with PIKE-A and phosphorylates it on both Y682 and Y774 residues. Tyrosine phosphorylation in PIKE-A is required for its association with active fyn but not for Akt. Mutation of D into A in PIKE-A protects it from caspase cleavage and promotes cell survival. Thus, this finding provides a molecular mechanism accounting for the antiapoptotic action of src-family tyrosine kinase.

    Funded by: NINDS NIH HHS: R01, NS045627

    Cell death and differentiation 2007;14;2;368-77

  • 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 and Ye K

    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

    Phosphatidylinositol 3 (PI3)-kinase enhancer (PIKE) is a nuclear GTPase that enhances PI3-kinase activity in a GTP-dependent manner. Both PIKE-L and -A isoforms contain GTPase, pleckstrin homology (PH), ADP ribosylation factor-GTPase-activating protein, and two ankyrin repeats domains, and C-terminal ADP ribosylation factor-GTPase-activating protein activates its internal GTPase activity. However, whether PH domain modulates the intramolecular action and subsequently influences its downstream signalings remains elusive. Here we show that PH domain from PIKE-L robustly binds PI(3,4,5)P(3) and exclusively resides in the nucleus. By contrast, the mutant (K679,687N), unable to bind phosphoinositol lipids, translocates to the cytoplasm. This mutation substantially compromises the stimulatory effects on PI3-kinase by PIKE-L. Surprisingly, PH domain from PIKE-A distributes in the cytoplasm. Similar mutation in PH domain of PIKE-A abolishes its binding to PI(3,4,5)P(3) and significantly decreases its activation of Akt. Moreover, amplified PIKE-A from human cancers contains mutations and highly stimulates Akt kinase activity, correlating with its GTPase activity. Thus, phosphatidylinositols regulate PIKE GTPase activity, mediating its downstream PI3-kinase/Akt signaling through a feedback mechanism by binding to its PH domain.

    Funded by: NINDS NIH HHS: R01 NS045627

    Proceedings of the National Academy of Sciences of the United States of America 2005;102;46;16853-8

  • Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas.

    Knobbe CB, Trampe-Kieslich A and Reifenberger G

    Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany.

    Glioblastomas frequently carry genetic alterations resulting in an aberrant activation of the phosphoinositol-3-kinase (Pi3k)/protein kinase B (Akt) signalling pathway, including most notably phosphatase and tensin homolog (PTEN) mutation, epidermal growth factor receptor (EGFR) amplification and rearrangement, as well as carboxyl-terminal modulator protein (CTMP) hypermethylation [Knobbe et al., (2004) Hypermethylation and transcriptional downregulation of the carboxyl-terminal modulator protein gene in glioblastomas. J Natl Cancer Institute, 96, 483-486]. Here, we investigated two further Pi3k/Akt pathway genes, namely PIK3CA (3q26.3) and phosphatidylinositol-3-kinase enhancer (PIKE) (CENTG1, 12q14), for genetic alteration and aberrant expression in a series of 97 primary glioblastomas. Single strand conformation polymorphism (SSCP) analysis of PIK3CA revealed somatic mutations in five tumours (5%). Twelve glioblastomas (12%) showed amplification of PIKE with invariable co-amplification of the adjacent CDK4 gene. All tumours with PIKE amplification as well as the vast majority of glioblastomas without amplification demonstrated increased expression of PIKE-A but not PIKE-S/L transcripts as compared with non-neoplastic brain tissue. Taken together, our data support an important role of PIK3CA and PIKE gene aberrations in the molecular pathogenesis of primary glioblastomas.

    Neuropathology and applied neurobiology 2005;31;5;486-90

  • The Arf GAPs AGAP1 and AGAP2 distinguish between the adaptor protein complexes AP-1 and AP-3.

    Nie Z, Fei J, Premont RT and Randazzo PA

    Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

    ADP ribosylation factors (Arf) regulate membrane trafficking at multiple intracellular sites by recruiting coat proteins to membranes. The site-specific regulation of Arf is thought to be mediated by regulatory proteins including the guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Here, we test this hypothesis by comparing the site of action of the Arf GAP AGAP2 to the closely related AGAP1. AGAP1 has previously been found to associate with the adaptor protein complex AP-3 and regulate the function of AP-3 endosomes. We found that AGAP2 directly interacted with AP-1. AGAP2 colocalized with AP-1, transferrin receptor and Rab4 on endosomes. Overexpression of AGAP2 changed the intracellular distribution of AP-1 and promoted Rab4-dependent fast recycling of transferrin. Based on these results, we concluded that the closely related Arf GAPs, AGAP1 and AGAP2, distinguish between these related heterotetrameric adaptor protein complexes to specifically regulate AP-3 endosomes and AP-1 recycling endosomes.

    Journal of cell science 2005;118;Pt 15;3555-66

  • PIKE GTPase signaling and function.

    Ahn JY and Ye K

    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

    PIKE (PI 3-Kinase Enhancer) is a recently identified brain specific nuclear GTPase, which binds PI 3-kinase and stimulates its lipid kinase activity. Nerve growth factor treatment leads to PIKE activation by triggering the nuclear translocation of phospholipase C-gamma1 (PLC-gamma1), which acts as a physiologic guanine nucleotide exchange factor (GEF) for PIKE through its SH3 domain. To date, three forms of PIKE have been characterized: PIKE-S, PIKE-L and PIKE-A. PIKE-S is initially identified shorter isoform. PIKE-L, a longer isoform of PIKE gene, differs from PIKE-S by C-terminal extension containing Arf-GAP (ADP ribosylation factor-GTPase Activating Protein) and two ankyrin repeats domains. In contrast to the exclusive nuclear localization of PIKE-S, PIKE-L occurs in both the nucleus and the cytoplasm. PIKE-L physiologically associates with Homer 1, an mGluR I binding adaptor protein. The Homer/PIKE-L complex couples PI 3-kinase to mGluR I and regulates a major action of group I mGluRs, prevention of neuronal apoptosis. More recently, a third PIKE isoform, PIKE-A was identified in human glioblastoma multiforme brain cancers. Unlike the brain specific PIKE-L and -S isoforms, PIKE-A distributes in various tissues. PIKE-A contains the same domains present in PIKE-L but lacks N-terminal proline-rich domain (PRD), which binds PI 3-kinase and PLC-gamma1. Instead, PIKE-A specifically binds to active Akt and upregulates its activity in a GTP-dependent manner, mediating human cancer cell invasion and preventing apoptosis. Thus, PIKE extends its roles from the nucleus to the cytoplasm, mediating cellular processes from cell invasion to programmed cell death.

    Funded by: NINDS NIH HHS: R01 NS045627

    International journal of biological sciences 2005;1;2;44-50

  • The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

    Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Morrin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J and MGC Project Team

    The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

    Funded by: PHS HHS: N01-C0-12400

    Genome research 2004;14;10B;2121-7

  • PIKE-A is amplified in human cancers and prevents apoptosis by up-regulating Akt.

    Ahn JY, Hu Y, Kroll TG, Allard P and Ye K

    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.

    PIKE-A (PIKE-activating Akt), an isoform of PIKE GTPase that enhances phosphatidylinositol 3-kinase (PI3-kinase) activity, specifically binds to active Akt but not PI3-kinase. PIKE-A stimulates Akt activity in a GTP-dependent manner and promotes invasiveness of cancer cell lines. Here, we show that PIKE-A is amplified in a variety of human cancers and that amplified PIKE-A directly stimulates Akt and inhibits apoptosis compared to cells with normal PIKE-A copy number. Overexpression of PIKE-A wild-type but not dominant-negative mutant stimulates Akt activity and prevents apoptosis. Moreover, knockdown of PIKE-A diminishes Akt activity and increases apoptosis. Our findings suggest that PIKE-A amplification contributes to cancer cell survival and progression by inhibiting apoptosis through up-regulating Akt.

    Proceedings of the National Academy of Sciences of the United States of America 2004;101;18;6993-8

  • 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 and Ye K

    Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

    Akt/PKB is a crucial regulator of diverse cellular processes and contributes to cancer progression. Activation of Akt is essentially dependent on phosphatidylinositol (PI) 3-kinase signaling. Here, we describe a novel mediator of Akt that is independent of PI 3-kinase. This mediator, PIKE-A, is a PIKE isoform and contains GTPase, pleckstrin homology, ArfGAP, and ankyrin repeats domains. PIKE-A directly binds to activated Akt but not PI 3-kinase in a guanine nucleotide-dependent way and stimulates the kinase activity of Akt. Overexpression of PIKE-A enhances Akt activity and promotes cancer cell invasion, whereas dominant-negative PIKE-A and PIKE-A knockdown markedly inhibit these processes. Our results demonstrate that PIKE-A is a physiologic regulator of Akt and an oncogenic effector of cell invasion.

    Funded by: NINDS NIH HHS: R01 NS045627

    The Journal of biological chemistry 2004;279;16;16441-51

  • Complete sequencing and characterization of 21,243 full-length human cDNAs.

    Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T and Sugano S

    Helix Research Institute, 1532-3 Yana, Kisarazu, Chiba 292-0812, Japan.

    As a base for human transcriptome and functional genomics, we created the "full-length long Japan" (FLJ) collection of sequenced human cDNAs. We determined the entire sequence of 21,243 selected clones and found that 14,490 cDNAs (10,897 clusters) were unique to the FLJ collection. About half of them (5,416) seemed to be protein-coding. Of those, 1,999 clusters had not been predicted by computational methods. The distribution of GC content of nonpredicted cDNAs had a peak at approximately 58% compared with a peak at approximately 42%for predicted cDNAs. Thus, there seems to be a slight bias against GC-rich transcripts in current gene prediction procedures. The rest of the cDNAs unique to the FLJ collection (5,481) contained no obvious open reading frames (ORFs) and thus are candidate noncoding RNAs. About one-fourth of them (1,378) showed a clear pattern of splicing. The distribution of GC content of noncoding cDNAs was narrow and had a peak at approximately 42%, relatively low compared with that of protein-coding cDNAs.

    Nature genetics 2004;36;1;40-5

  • PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis.

    Rong R, Ahn JY, Huang H, Nagata E, Kalman D, Kapp JA, Tu J, Worley PF, Snyder SH and Ye K

    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Room 145, Whitehead Building, 615 Michael Street, Atlanta, Georgia 30322, USA.

    Phosphoinositide 3 kinase enhancer (PIKE) is a recently identified nuclear GTPase that activates nuclear phosphoinositide 3-kinase (PI3 kinase). We have identified, cloned and characterized a new form of PIKE, designated PIKE-L, which, unlike the nuclear PIKE-S, localizes to both the cytoplasm and the nucleus. We demonstrate physiologic binding of PIKE-L to Homer, an adaptor protein known to link metabotropic glutamate receptors to multiple intracellular targets including the inositol 1,4,5-trisphosphate receptor (IP3R). We show that activation of group I metabotropic glutamate receptors (mGluRIs) enhances formation of an mGluRI-Homer-PIKE-L complex, leading to activation of PI3 kinase activity and prevention of neuronal apoptosis. Our findings indicate that this complex mediates the well-known ability of agonists of mGluRI to prevent neuronal apoptosis.

    Funded by: NINDS NIH HHS: R01 NS045627

    Nature neuroscience 2003;6;11;1153-61

  • GGAPs, a new family of bifunctional GTP-binding and GTPase-activating proteins.

    Xia C, Ma W, Stafford LJ, Liu C, Gong L, Martin JF and Liu M

    Center for Cancer Biology and Nutrition, Alkek Institute of Biosciences and Technology, and Department of Medical Biochemistry and Genetics, Texas A&M University System Health Science Center, Houston, Texas 77030, USA.

    G proteins are molecular switches that control a wide variety of physiological functions, including neurotransmission, transcriptional activation, cell migration, cell growth. and proliferation. The ability of GTPases to participate in signaling events is determined by the ratio of GTP-bound to GDP-bound forms in the cell. All known GTPases exist in an inactive (GDP-bound) and an active (GTP-bound) conformation, which are catalyzed by guanine nucleotide exchange factors and GTPase-activating proteins (GAPs), respectively. In this study, we identified and characterized a new family of bifunctional GTP-binding and GTPase-activating proteins, named GGAP. GGAPs contain an N-terminal Ras homology domain, called the G domain, followed by a pleckstrin homology (PH) domain, a C-terminal GAP domain, and a tandem ankyrin (ANK) repeat domain. Expression analysis indicates that this new family of proteins has distinct cell localization, tissue distribution, and even message sizes. GTPase assays demonstrate that GGAPs have high GTPase activity through direct intramolecular interaction of the N-terminal G domain and the C-terminal GAP domain. In the absence of the GAP domain, the N-terminal G domain has very low activity, suggesting a new model of GGAP protein regulation via intramolecular interaction like the multidomain protein kinases. Overexpression of GGAPs leads to changes in cell morphology and activation of gene transcription.

    Funded by: NHLBI NIH HHS: 5R01 HL64792, R01 HL064792

    Molecular and cellular biology 2003;23;7;2476-88

  • AGAP1, an endosome-associated, phosphoinositide-dependent ADP-ribosylation factor GTPase-activating protein that affects actin cytoskeleton.

    Nie Z, Stanley KT, Stauffer S, Jacques KM, Hirsch DS, Takei J and Randazzo PA

    Laboratories of Cellular Oncology and Biochemistry, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.

    We have identified three members of the AGAP subfamily of ASAP family ADP-ribosylation factor GTPase-activating proteins (Arf GAPs). In addition to the Arf GAP domain, these proteins contain GTP-binding protein-like, ankyrin repeat and pleckstrin homology domains. Here, we have characterized the ubiquitously expressed AGAP1/KIAA1099. AGAP1 had Arf GAP activity toward Arf1>Arf5>Arf6. Phosphatidylinositol 4,5-bisphosphate and phosphatidic acid synergistically stimulated GAP activity. As found for other ASAP family Arf GAPs, the pleckstrin homology domain was necessary for activity. Deletion of the GTP-binding protein-like domain affected lipid dependence of Arf GAP activity. In vivo effects of AGAP1 were distinct from other ASAP family Arf GAPs. Overexpressed AGAP1 induced the formation of and was associated with punctate structures containing the endocytic markers transferrin and Rab4. AP1 was redistributed from the trans-Golgi to the punctate structures. Like other ASAP family members, AGAP1 overexpression inhibited the formation of PDGF-induced ruffles. However, distinct from other ASAP family members, AGAP1 also induced the loss of actin stress fibers. Thus, AGAP1 is a phosphoinositide-dependent Arf GAP that impacts both the endocytic compartment and actin.

    The Journal of biological chemistry 2002;277;50;48965-75

  • Phospholipase C gamma 1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE.

    Ye K, Aghdasi B, Luo HR, Moriarity JL, Wu FY, Hong JJ, Hurt KJ, Bae SS, Suh PG and Snyder SH

    Johns Hopkins University School of Medicine, Department of Neuroscience, 725 N. Wolfe Street, Baltimore, Maryland 21205, USA.

    Phospholipase C gamma 1 (PLC-gamma 1) hydrolyses phosphatidylinositol-4,5-bisphosphate to the second messengers inositol-1,4,5-trisphosphate and diacylglycerol. PLC-gamma 1 also has mitogenic activity upon growth-factor-dependent tyrosine phosphorylation; however, this activity is not dependent on the phospholipase activity of PLC-gamma 1, but requires an SH3 domain. Here, we demonstrate that PLC-gamma 1 acts as a guanine nucleotide exchange factor (GEF) for PIKE (phosphatidylinositol-3-OH kinase (PI(3)K) enhancer). PIKE is a nuclear GTPase that activates nuclear PI(3)K activity, and mediates the physiological activation by nerve growth factor (NGF) of nuclear PI(3)K activity. This enzymatic activity accounts for the mitogenic properties of PLC-gamma 1.

    Nature 2002;415;6871;541-4

  • Pike. A nuclear gtpase that enhances PI3kinase activity and is regulated by protein 4.1N.

    Ye K, Hurt KJ, Wu FY, Fang M, Luo HR, Hong JJ, Blackshaw S, Ferris CD and Snyder SH

    Johns Hopkins University School of Medicine, Department of Neuroscience, North Wolfe Street 21205, Baltimore, MD, USA.

    While cytoplasmic PI3Kinase (PI3K) is well characterized, regulation of nuclear PI3K has been obscure. A novel protein, PIKE (PI3Kinase Enhancer), interacts with nuclear PI3K to stimulate its lipid kinase activity. PIKE encodes a 753 amino acid nuclear GTPase. Dominant-negative PIKE prevents the NGF enhancement of PI3K and upregulation of cyclin D1. NGF treatment also leads to PIKE interactions with 4.1N, which has translocated to the nucleus, fitting with the initial identification of PIKE based on its binding 4.1N in a yeast two-hybrid screen. Overexpression of 4.1N abolishes PIKE effects on PI3K. Activation of nuclear PI3K by PIKE is inhibited by the NGF-stimulated 4.1N translocation to the nucleus. Thus, PIKE physiologically modulates the activation by NGF of nuclear PI3K.

    Funded by: NCI NIH HHS: CA00266; NIDA NIH HHS: DA-00074

    Cell 2000;103;6;919-30

  • 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 and Meltzer PS

    Laboratory of Cancer Genetics, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-4470, USA.

    We used a combination of sequence analysis and exon trapping in an effort to determine the complete transcript map for a cosmid (6E5) derived from 12q13.3, a region of DNA sequence amplification in human cancers. This cosmid, previously known to contain three genes (CDK4, SAS, and OS9), was sequenced, and that information was used for computer-assisted analysis. In addition, 6E5 was subjected to both internal and 3'-terminal exon-trapping protocols, and the results of these studies were used to guide cDNA cloning experiments. These studies demonstrate that this cosmid is derived from a remarkably gene-dense region and add two new transcripts (KIAA0167 and 6E5.2) to the list of sequences that are expressed in tumors bearing amplification of this region.

    Funded by: NHGRI NIH HHS: HG00313

    Genomics 1997;42;2;295-301

  • 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 and Nomura N

    Kazusa DNA Research Institute, Chiba, Japan.

    As part of our continuing efforts to accumulate information on the coding region of unidentified human genes, we newly determined the sequences of 40 cDNA clones of human cell line KG-1 which correspond to relatively long and nearly full-length transcripts, and predicted the coding sequences of the corresponding genes, named KIAA0161 to 0200. The average size of the cDNA clones analyzed was approximately 5.0 kb. A computer search of the sequences in public databases indicated that the sequences of 20 genes were unrelated to any reported genes, while the remaining 20 genes carried sequences which show some similarities to known genes. Among the genes in the latter category, KIAA0167 contained a Zn-finger motif with significant structural similarity to that of the yeast transcription factor GCS1, and KIAA0189 was classified into the RhoGAP gene family. Stretches of typical CAG (Gln) repeats, which were often correlated with genetic disorders, were found in KIAA0181 and KIAA0192. Another novel repeat composed of alternating Arg and Glu was identified in KIAA0182. Northern hybridization analysis demonstrated that 10 genes are expressed in a cell- or tissue-specific manner.

    DNA research : an international journal for rapid publication of reports on genes and genomes 1996;3;1;17-24

Gene lists (6)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000059 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus 748
L00000061 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus (ortho) 984
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
L00000071 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list (ortho) 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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