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PI3 kinase enhancer–Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis

Abstract

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.

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Figure 1: Cloning and characterization of PIKE-L.
Figure 2: PIKE-L localizes in both cell body and synapses of hippocampal neurons.
Figure 3: PIKE-L binds to Homer 1.
Figure 4: Homer-binding motif PKPF mediates PIKE-L and Homer 1 interaction.
Figure 5: mGluRI agonist activates PI3 kinase through Homer 1-PIKE-L complex.
Figure 6: Homer-binding motif PKPF mediates mGluR-stimulated PI3 kinase activation.
Figure 7: Activation of mGluR stimulates formation of mGluR-Homer-PIKE-L complex.
Figure 8: PIKE-L and Homer 1 complex is required for quisqualate to activate PI3 kinase and protect neurons from apoptosis.

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Acknowledgements

This work was supported by the US National Institutes of Health (RO1 NS045627 to K.Y.). We are grateful to P.A. Wade for discussion.

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Correspondence to Keqiang Ye.

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Rong, R., Ahn, JY., Huang, H. et al. PI3 kinase enhancer–Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis. Nat Neurosci 6, 1153–1161 (2003). https://doi.org/10.1038/nn1134

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