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

Rong, Rong; Ahn, Jee Yin; Huang, Honglian; Nagata, Eiichiro; Kalman, Daniel; Kapp, Judith A.; Tu, Jiancheng; Worley, Paul F.; Snyder, Solomon H.; Ye, Keqiang

doi:10.1038/nn1134

Cited by 265 publications

(309 citation statements)

References 43 publications

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“…Our previous work demonstrated that PIKE enhances PI 3-kinase/Akt signaling cascade and promotes cell survival (Rong et al, 2003;Ahn et al, 2004c). These findings suggested that PIKE is a proto-oncogene.…”

Section: Discussionmentioning

confidence: 90%

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

Liu

Hao

et al. 2007

Oncogene

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Section: Discussionmentioning

confidence: 90%

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

Liu

Hao

et al. 2007

Oncogene

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“…Multimerization of long Homer isforms through their C-terminal CC-domains mediates the cell membrane localization and postsynaptic density clustering of glutamate receptors and proteins involved in their intracellular signaling cascades (Abe et al, 2003;Naisbitt et al, 1999;Rong et al, 2003;Shiraishi et al, 2003a, b). Moreover, long Homer isoform expression is also necessary for the normal formation of glutamatergic synapses during development (Shiraishi et al, 2004).…”

Section: Homer Proteins and The Regulation Of Glutamate Transmissionmentioning

confidence: 99%

“…Both long and short Homer isoforms interact through an Ena/VASP1 homology (EVH1) domain with a long proline-rich motif located on Group 1 metabotropic glutamate receptors (mGluRs), inositol-1,4,5-triphosphate (IP3) and ryanodine receptors, TRP cation channels and Shank (Brakeman et al, 1997;Hwang et al, 2003;Kammermeier et al, 2000;Kato et al, 1998;Tu et al, 1998Tu et al, , 1999Xiao et al, 1998;Yuan et al, 2003). Long Homer isoforms contain a coiled-coil (CC) domain at their Cterminus that enables the cell membrane localization and clustering of glutamate receptors and proteins involved in their intracellular signaling cascades (Abe et al, 2003;Naisbitt et al, 1999;Rong et al, 2003;Shiraishi et al, 2003a, b). In contrast, short Homer1 isoforms lack the CCdomain and the ability to multimerize (Bottai et al, 2002;Xiao et al, 1998) and thus function as a natural dominant negative of Homer multimers to influence synaptic plasticity (Brakeman et al, 1997;Hennou et al, 2003;Sala et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Homer Isoforms Differentially Regulate Cocaine-Induced Neuroplasticity

Szumlinski

Abernathy

Oleson

et al. 2005

Neuropsychopharmacol

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Homer proteins modulate neuroplasticity in excitatory synapses and are dynamically regulated by cocaine. Whereas acute cocaine elevates immediate-early gene (short) isoforms of Homer1 in the nucleus accumbens, withdrawal from repeated cocaine administration downregulates the expression of constitutive Homer1 isoforms. The present study determined whether or not this downregulation in constitutive Homer expression in the accumbens is necessary for enduring alterations in cocaine-induced changes in the brain and behavior. The long vs short Homer isoforms were overexpressed in the rat nucleus accumbens during drug abstinence, and the adaptations elicited by repeated cocaine on glutamate transmission and motor behavior were measured. It was found that both chronic and acute overexpression of constitutive, but not short, Homer isoforms abolished cocaine-induced sensitization of locomotor hyperactivity and prevented the development of glutamate abnormalities in the accumbens, including the reduction in basal extracellular glutamate content and the sensitized glutamate response to a subsequent cocaine challenge injection. Together, these data indicate that the enduring reduction of long Homer isoforms in the nucleus accumbens of cocaine-withdrawn rats is necessary for the expression of cocaine-induced neuroplasticity.

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“…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.…”

mentioning

confidence: 99%

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

et al. 2008

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

Cited by 265 publications

References 43 publications

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

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

Homer Isoforms Differentially Regulate Cocaine-Induced Neuroplasticity

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

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