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

Liu, X; Hu, Yinghong; Hao, Chunhai; Rempel, Sandra A.; Ye, K

doi:10.1038/sj.onc.1210290

Cited by 45 publications

(68 citation statements)

References 24 publications

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“…We have reported that AGAP2 binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab4-dependent endosomal trafficking (16). Studies from other groups have indicated that AGAP2 is overexpressed in different human cancers, including glioblastoma, and that AGAP2 enhances the invasion of glioblastoma cells (17,18).In this study, we tested the hypothesis that AGAP2 regulates focal adhesion remodeling and cell migration. We find that AGAP2 forms a complex with FAK, increases the FAK activity, and provokes the focal adhesion disassembly that may lead to increased cell migration.…”

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confidence: 95%

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Arf GTPase-activating Protein AGAP2 Regulates Focal Adhesion Kinase Activity and Focal Adhesion Remodeling

Zhu

Kim

et al. 2009

Journal of Biological Chemistry

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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 plateletderived 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.Focal adhesions are macromolecular structures that connect actin cytoskeleton to the extracellular matrix and play an important role in cell migration (1). Components of focal adhesions include signaling proteins such as focal adhesion kinase (FAK), 3 c-Src, and paxillin, as well as structural proteins such as talin and vinculin (2, 3). Focal adhesions are constantly formed and disassembled (i.e. remodeled) at the leading edge of migrating cells, and they are disassembled at the trailing edge during the cell migration (4, 5). Available evidence demonstrates that the remodeling of focal adhesions is regulated by FAK (6) and Arf-directed GTPase-activating proteins (Arf GAPs) (7).FAK is a member of the Src family nonreceptor tyrosine kinases whose activities are regulated by intra-molecular phosphorylation (8). Autophosphorylation of FAK on tyrosine residue 397 provides docking sites for Src homology 2 domain-containing proteins, including c-Src. After binding to FAK, c-Src phosphorylates FAK on Tyr-576 and Tyr-577 to activate fully the intrinsic kinase activity of FAK (9). Cellular functions of FAK are many and include cell migration, survival, and proliferation; and activation of FAK occurs upon integrin clustering or stimulation of cell surface receptors such as the epidermal growth factor (EGF) or plateletderived growth factor (PDGF) receptors. FAK activation following integrin clustering results in recruitment of structural and signaling proteins that collectively contribute to the formation of the focal adhesions (10). In FAK null cells, focal adhesions are formed but cannot disassemble (11), suggesting that FAK is required for the focal adhesion...

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Arf GTPase-activating Protein AGAP2 Regulates Focal Adhesion Kinase Activity and Focal Adhesion Remodeling

Zhu

Kim

et al. 2009

Journal of Biological Chemistry

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“…Frequently coamplified with CDK4 is CENTG1. CENTG1 encodes PIKE, which activates AKT and PI3 kinase (8), thus promoting cell growth and transformation (9).…”

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Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship

Kim

Huang

Jiang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

220

173

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Using a multidimensional genomic data set on glioblastoma from The Cancer Genome Atlas, we identified hsa-miR-26a as a cooperating component of a frequently occurring amplicon that also contains CDK4 and CENTG1, two oncogenes that regulate the RB1 and PI3 kinase/AKT pathways, respectively. By integrating DNA copy number, mRNA, microRNA, and DNA methylation data, we identified functionally relevant targets of miR-26a in glioblastoma, including PTEN, RB1, and MAP3K2/MEKK2. We demonstrate that miR-26a alone can transform cells and it promotes glioblastoma cell growth in vitro and in the mouse brain by decreasing PTEN, RB1, and MAP3K2/MEKK2 protein expression, thereby increasing AKT activation, promoting proliferation, and decreasing c-JUN Nterminal kinase-dependent apoptosis. Overexpression of miR-26a in PTEN-competent and PTEN-deficient glioblastoma cells promoted tumor growth in vivo, and it further increased growth in cells overexpressing CDK4 or CENTG1. Importantly, glioblastoma patients harboring this amplification displayed markedly decreased survival. Thus, hsa-miR-26a, CDK4, and CENTG1 comprise a functionally integrated oncomir/oncogene DNA cluster that promotes aggressiveness in human cancers by cooperatively targeting the RB1, PI3K/AKT, and JNK pathways.

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“…42 Among these isoforms, the short and long forms of PIKE have been found in neuronal tissue. 35,43 PIKE-A has been found in various tissues and acts as a proto-oncogene. 43 PIKE-A is the only isoform lacking the N-terminal PRDs.…”

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confidence: 99%

“…35,43 PIKE-A has been found in various tissues and acts as a proto-oncogene. 43 PIKE-A is the only isoform lacking the N-terminal PRDs. 42 In the present Figure 6.…”

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confidence: 99%

PIKE mediates EGFR proliferative signaling in squamous cell carcinoma cells

Xie

Jiang

et al. 2012

Oncogene

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One of the key drivers for squamous cell carcinoma (SCC) proliferation is activation of the epidermal growth factor receptor (EGFR), a known proto-oncogene. However, the mechanism of EGFR-dependent SCC proliferation remains unclear. Our previous studies indicate that epidermal growth factor (EGF)-induced SCC cell proliferation requires the SH3 domain of phospholipase C-g1 (PLC-g1), but not its catalytic activity. The SH3 domain of PLC-g1 is known to activate the short form of nuclear phosphatidylinositol 3-kinase enhancer (PIKE) that enhances the activity of nuclear class Ia phosphatidylinositol 3-kinase (PI3K) required for proliferation. However, PIKE has been described for more than a decade to be present exclusively in neuronal cells. In the present study, we found that PIKE was highly expressed in malignant human keratinocytes (SCC4 and SCC12B2) but had low expression in normal human keratinocytes. Immunohistochemical analysis showed strong nuclear staining of PIKE in human epidermal and tongue SCC specimens but little staining in the adjacent non-cancerous epithelium. Treatment of SCC4 cells with EGF-induced translocation of PLC-g1 to the nucleus and binding of PLC-g1 to the nuclear PIKE. Knockdown of PLC-g1 or PIKE blocked EGF-induced activation of class Ia PI3K and protein kinase C-z and phosphorylation of nucleolin in the nucleus as well as EGF-induced SCC cell proliferation. However, inhibition of the catalytic activity of PLC-g1 had little effect. These data suggest that PIKE has a critical role in EGF-induced SCC cell proliferation and may function as a proto-oncogene in SCC.

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

Cited by 45 publications

References 24 publications

Arf GTPase-activating Protein AGAP2 Regulates Focal Adhesion Kinase Activity and Focal Adhesion Remodeling

Arf GTPase-activating Protein AGAP2 Regulates Focal Adhesion Kinase Activity and Focal Adhesion Remodeling

Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship

PIKE mediates EGFR proliferative signaling in squamous cell carcinoma cells

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