Phospholipase Cγ1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE

Ye, Keqiang; Aghdasi, Bahman; Luo, Hongbo; Moriarity, John L.; Wu, Frederick Y.; Hong, Jenny J.; Hurt, K. Joseph; Bae, Sun Sik; Suh, Pann Ghill; Snyder, Solomon H.

doi:10.1038/415541a

Cited by 143 publications

(129 citation statements)

References 26 publications

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“…However, PIKE has been described for more than a decade to be present exclusively in neuronal cells and is activated by nerve growth factor-induced neuronal cell proliferation. 34,35 In the present study, we found that PIKE is highly expressed in SCC cells and mediates EGFR-dependent SCC cell proliferation. RESULTS PIKE is highly expressed in human SCC cells but at a low level in normal human keratinocytes The SH3 domain of PLC-g1 has been found to activate nuclear PIKE that activates nuclear class Ia PI3K, which in turn, triggers signaling cascades mediating neuronal cell proliferation.…”

Section: Introductionsupporting

confidence: 51%

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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Section: Introductionsupporting

confidence: 51%

PIKE mediates EGFR proliferative signaling in squamous cell carcinoma cells

Xie

Jiang

et al. 2012

Oncogene

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“…PI3-kinase was immunoprecipitated with rabbit anti-p110 from the cell extract, and washed with the following buffers: 3 times with buffer A (PBS, 1% NP-40, 1 mM dithiothreitol (DTT)); 2 times with buffer B (PBS, 0.5 M LiCl, 1 mM DTT); and 2 times with buffer C (10 mM Tris-HCl, pH 7.4, 0.1 M NaCl, 1 mM DTT). Subsequent steps were performed as described 12 .…”

Section: Pi 3-kinase Assaymentioning

confidence: 99%

“…PIKE activates PI 3-kinase in a GTP-dependent manner 11 . PLC-γ1 acts as a physiological guanine nucleotide exchange factor (GEF) for PIKE 12 . Recently, it has been shown that netrin-1 induces activation of PLC-γ1, which is mediated by DCC but not UNC5B or neogenin 24.…”

mentioning

confidence: 99%

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

et al. 2008

Self Cite

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Netrins, a family of secreted molecules, play critical roles in axon guidance and cell migration during neuronal development 1,2. In addition to its role as a chemotropic molecule, netrin-1 also acts as a survival factor 3-7 . Both UNC5 (i.e. UNC5A, B, C or D) and DCC are transmembrane receptors for netrin-1 8 ,9. In the absence of netrin-1, DCC and UNC5 act as dependence receptors and trigger apoptosis 3,6, 10 . 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 activation of PI 3-kinase signaling, prevents UNC5B's proapoptotic activity and enhances neuronal survival. Moreover, this process tightly relies on Fyn as 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. PIKE-L is a brain specific GTPase, which binds and stimulates PI 3-kinase in a GTP-dependent manner 11, 12 . PIKE-L binds Homer, an adaptor protein for metabotropic glutamate receptor (mGluR). Activation of mGluRIs enhances formation of an mGluRI-Homer-PIKE-L complex, leading to activation of PI 3-kinase and prevention of neuronal apoptosis 13 . PIKE is also a substrate for caspases. PIKE can be phosphorylated on tyrosine residues by Fyn, leading to its resistance to caspase cleavage 14. To search for PIKE-L-binding proteins, we conducted yeast two-hybrid screening using GTPase domain as bait. Four out of twelve clones are both His and β-gal positive, one of which encodes the C-terminus of UNC5B ( Figure 1A). In HEK293 cells, transfected GFP-PIKE-L selectively binds to 569-946 fragment of UNC5B but not other fragments. Compared to the binding by the C-terminal motif (a.a. 569-946), truncation of death domain (a.a. 854-946) decreases UNC5B affinity to PIKE-L. Reciprocal immunoprecipitation reveals that the interaction occurs no matter PIKE-L or UNC5B is precipitated by its antibody ( Figure 1B, middle panels). Full-length UNC5B and its C-terminal fragment released after caspase cleavage 5 , 7 specifically interact with GTPase domain but not with other regions of PIKE-L, consistent with our yeast two-hybrid findings ( Figure 1B, right panels). We also 5To whom all correspondence should be addressed, Phone: 404-712-2814; Fax: 404-712-2979, kye@emory observed the robust interaction between endogenous PIKE-L and UNC5B in both the cortex and hippocampus of rat brain ( Figure 1C). Immunostaining of hippocampal and cortical primary neurons reveals that PIKE-L and UNC5B colocalize in the cell body and throughout all neuronal processes ( Figure 1D, left panel). The staining is specific as GST-PIKE-L (a.a. 268-384) antigen but not control GST abolishes PIKE-L staining in neurons ( Figure 1D, right panels).To examine whether netrin-1 modulates PIKE-L interaction with UNC5B, we cotransfected UNC5B into...

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“…In PC12 cells, NGF treatment elicits powerful anti-apoptotic signaling cascades [Patapoutian and Reichardt, 2001]. In response to NGF, PI-PLCg1 translocates to the nucleus where it acts as a physiological guanine-nucleotide-exchange factor for PIKE-S [Ye et al, 2002]. PIKE-S is a nuclear-specific GTPase that enhances PI3K activity and is regulated by protein 4.1N [Ye et al, 2000;Ye and Snyder, 2004].…”

Section: New Roles For Nuclear Pi3k Andmentioning

confidence: 99%

Nuclear inositol lipid metabolism: More than just second messenger generation?

Martelli

Follo

Evangelisti

et al. 2005

J of Cellular Biochemistry

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A distinct polyphosphoinositide cycle is present in the nucleus, and growing evidence suggests its importance in DNA replication, gene transcription, and apoptosis. Even though it was initially thought that nuclear inositol lipids would function as a source for second messengers, recent findings strongly indicate that lipids present in the nucleus also fulfil other roles. The scope of this review is to highlight the most intriguing advances made in the field over the last few years, such as the possibility that nuclear phosphatidylinositol (4,5) bisphosphate is involved in maintaining chromatin in a transcriptionally active conformation, the new emerging roles for intranuclear phosphatidylinositol (3,4,5) trisphosphate and phosphoinositide 3-kinase, and the evidence which suggests a tight relationship between a decreased level of nuclear phosphoinositide specific phospholipase C-b1 and the evolution of myelodisplastic syndrome into acute myeloid leukemia.

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Phospholipase Cγ1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE

Cited by 143 publications

References 26 publications

PIKE mediates EGFR proliferative signaling in squamous cell carcinoma cells

PIKE mediates EGFR proliferative signaling in squamous cell carcinoma cells

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

Nuclear inositol lipid metabolism: More than just second messenger generation?

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