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First published online December 15, 2003
doi: 10.1242/10.1242/jcs.00924

Journal of Cell Science 117, 155-161 (2004)
Published by The Company of Biologists 2004
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PIKE GTPase: a novel mediator of phosphoinositide signaling

Keqiang Ye1,* and Solomon H. Snyder2

1 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA
2 Departments of Neuroscience, Pharmacology and Molecular Science, and Psychiatry, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA



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  		Fig. 1. PIKE-binding proteins. Protein 4.1N binds to the extreme N-terminal 23 amino acids of PIKE through its C-terminal domain. Both subunits (p85 and p110) of PI 3-kinase directly interact with PIKE. Interestingly, the p85 subunit and protein 4.1N bind to the same region of PIKE. However, the structural requirements for PIKE binding to p110 differ somewhat from binding to p85, the N-terminal fragment from amino acids 24-262 being critical for p110 to bind to PIKE. In addition, the mGluR1- and mGluR5-associated protein Homer 1 binds to the proline-rich domain of PIKE (amino acids 187-190).

 


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  		Fig. 2. PLC-{gamma}1 and PI 3-kinase signaling cross-talk. Activated PI 3-kinase-generated D3-phosphatidylinositol lipids mediate a variety of cellular processes, including cell survival, cell proliferation, vesicle trafficking, motility and carbohydrate metabolism. PtdIns(3,4,5)P3 binds to PLC-{gamma}1 and is implicated in the cross-talk between PLC-{gamma}1 and PI 3-kinase. Moreover, it might also bind to the PH domain of PIKE and regulate its GTPase activity through a negative-feedback mechanism.

 


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  		Fig. 3. PIKE-L association with glutamate receptors. Homer dimers couple Ins(1,4,5)P3 receptor to mGluR1,5, and mediate intracellular Ca2+ signaling. Shank/Homer interactions link mGluR1,5 to NMDA receptors through PSD-95 and GKAP. PIKE-L/Homer interactions might link mGluR1,5 to the AMPA receptor GluR1 through the association of the N-terminus of PIKE and the C-terminal domain of 4.1N. This postsynaptic complex might regulate the communication between AMPA receptors and mGluRs.

 


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  		Fig. 4. The PIKE-L/Homer complex couples mGluR to PI 3-kinase and mediates neuronal survival. Through its EVH1 domain, dimerized Homer binds PIKE-L and mGluR1,5 via the `Homer-binding motif'. mGluR1,5 agonists trigger the formation of the PIKE-L/Homer complex and activate PI 3-kinase, enhancing neuronal survival.

 




© The Company of Biologists Ltd 2004