PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis.
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.
Rong
Rong
R
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Room 145, Whitehead Building, 615 Michael Street, Atlanta, Georgia 30322, USA.
Ahn
Jee-Yin
JY
Huang
Honglian
H
Nagata
Eiichiro
E
Kalman
Daniel
D
Kapp
Judith A
JA
Tu
Jiancheng
J
Worley
Paul F
PF
Snyder
Solomon H
SH
Ye
Keqiang
K
D000256:Adenoviridae / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000704:Analysis of Variance; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002458:Cell Fractionation / Q000379:methods; D002478:Cells, Cultured; D003001:Cloning, Molecular / Q000379:methods; D053938:DNA Fragmentation / Q000502:physiology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D000072233:Homer Scaffolding Proteins; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007668:Kidney; D007930:Leucine / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D009479:Neuropeptides / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011233:Precipitin Tests / Q000379:methods; D011392:Proline / Q000235:genetics; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019311:Staurosporine / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D014162:Transfection; D000077191:Wortmannin
D000730:Androstadienes; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D000072233:Homer Scaffolding Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; D016708:Synaptophysin; C104077:metabotropic glutamate receptor type 1; C033652:postsynaptic density proteins; D018698:Glutamic Acid; C121465:6-methyl-2-(phenylethynyl)pyridine; D016318:Quisqualic Acid; D011392:Proline; C499320:PARP1 protein, human; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019869:Phosphatidylinositol 3-Kinases; D007930:Leucine; D019311:Staurosporine; D000077191:Wortmannin