Cloning and Characterization of Postsynaptic Density 93, a Nitric Oxide Synthase Interacting Protein

Brenman, Jay E.; Christopherson, Karen S.; Craven, Sarah E.; McGee, Aaron W.; Bredt, David S.

doi:10.1523/jneurosci.16-23-07407.1996

Cited by 313 publications

(234 citation statements)

References 35 publications

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“…Reduced glutamate receptor phosphorylation, previously observed in GBM (35, 36), along with decreased phosphorylation of Dlg 2 (PSD-93), 3, and 4 (PSD-95) (37), and other neuron-specific proteins in our tumors likely reflect the differences in cellular composition between glioma and normal brain tissue (21). By comparison, phosphorylation of proteins involved in canonical oncogenic signaling networks, including ERK1/2 MAP kinases (T183/Y185 and T203/Y205 in the activation loop), PI3K regulatory subunit P85a, PDGFRα, and RTK scaffolds GAB1 and SHC, and cell cycle regulation (CDK1) were all increased in the tumor samples.…”

Section: Discussionsupporting

confidence: 54%

Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma

et al. 2016

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Glioblastoma (GBM) is the most common malignant primary brain cancer. With a median survival of about a year, new approaches to treating this disease are necessary. To identify signaling molecules regulating GBM progression in a genetically engineered murine model of proneural GBM, we quantified phosphotyrosine mediated signaling using mass spectrometry. Oncogenic signals, including phosphorylated ERK MAPK, PI3K, and PDGFR, were found to be increased in the murine tumors relative to brain. Phosphorylation of CDK1 pY15, associated with the G2 arrest checkpoint, was identified as the most differentially phosphorylated site, with a 14-fold increase in phosphorylation in the tumors. To assess the role of this checkpoint as a potential therapeutic target, syngeneic primary cell lines derived from these tumors were treated with MK-1775, an inhibitor of Wee1, the kinase responsible for CDK1 Y15 phosphorylation. MK-1775 treatment led to mitotic catastrophe, as defined by increased DNA damage and cell death by apoptosis. To assess the extensibility of targeting Wee1/CDK1 in GBM, patient-derived xenograft (PDX) cell lines were also treated with MK-1775. Although the response was more heterogeneous, on-target Wee1 inhibition led to decreased CDK1 Y15 phosphorylation and increased DNA damage and apoptosis in each line. These results were also validated in vivo, where single-agent MK-1775 demonstrated an anti-tumor effect on a flank PDX tumor model, increasing mouse survival by 1.74-fold. This study highlights the ability of unbiased quantitative phosphoproteomics to reveal therapeutic targets in tumor models, and the potential for Wee1 inhibition as a treatment approach in pre-clinical models of GBM.

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Section: Discussionsupporting

confidence: 54%

Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma

et al. 2016

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“…The double-band detected for PSD-93, in accordance with earlier reports, likely represent different splice variants of this protein. 62,63 Correlation analysis, using age, pH and PMI as independent measures, identified significant associations between PMI and NF-L expression in DLPFC (r = 0.50, P = 0.02) and PSD-93 and PMI in ACC (r = 0.45, P = 0.04). In addition, we found PSD-95 expression in ACC negatively associated with pH (r = 0.44, 0.048) (i.e., lower pH = increased PSD-95 concentration).…”

Section: Resultsmentioning

confidence: 99%

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

et al. 2006

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Abnormal expression of the N-Methyl-D-Aspartate (NMDA) receptor and its interacting molecules of the postsynaptic density (PSD) are thought to be involved in the pathophysiology of schizophrenia. Frontal regions of neocortex including dorsolateral prefrontal (DLPFC) and anterior cingulate cortex (ACC) are essential for cognitive and behavioral functions that are affected in schizophrenia. In this study, we have measured protein expression of two alternatively spliced isoforms of the NR1 subunit (NR1 C2 and NR1 C2 0 ) as well as expression of the NR2A-D subunits of the NMDA receptor in DLPFC and ACC in post-mortem samples from elderly schizophrenic patients and a comparison group. We found significantly increased expression of NR1 C2 0 but not of NR1 C2 in ACC, suggesting altered NMDA receptor cell membrane expression in this cortical area. We did not find significant changes in the expression of either of the NR1 isoforms in DLPFC. We did not detect changes of any of the NR2 subunits studied in either cortical area. In addition, we studied expression of the NMDAinteracting PSD molecules NF-L, SAP102, PSD-95 and PSD-93 in ACC and DLPFC at both transcriptional and translational levels. We found significant changes in the expression of NF-L in DLPFC, and PSD-95 and PSD-93 in ACC; increased transcript expression was associated with decreased protein expression, suggesting abnormal translation and/or accelerated protein degradation of these molecules in schizophrenia. Our findings suggest abnormal regional processing of the NMDA receptor and its associated PSD molecules, possibly involving transcription, translation, trafficking and protein stability in cortical areas in schizophrenia.

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“…While neither deletion of Homer1 nor Homer2 alters total NMDA receptor subunit expression within the NAC or PFC (Table 3) [34,176], Homer2 deletion reduces the NAC plasma membrane expression of NR2a and NR2b NMDA receptor subunits in vivo [38]. Through the Shank-GKAP-PSD95 complex, NR2 subunits colocalize with nitric oxidase synthase-1 (NOS-1) [177][178][179], an enzyme responsible for the synthesis of the retrograde messenger nitric oxide (NO) [180,181]. Thus, one testable hypothesis to account for the effects of Homer deletion upon basal and stimulated corticoaccumbens glutamate transmission relates to alterations in NMDA-mediated NO retrograde signaling [182,183].…”

Section: Homer Regulation Of Corticoaccumbens Glutamate In Vivomentioning

confidence: 99%

Homers regulate drug-induced neuroplasticity: Implications for addiction

Szumlinski

Ary

Lominac

2008

Biochemical Pharmacology

118

160

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Drug addiction is a chronic, relapsing disorder, characterized by an uncontrollable motivation to seek and use drugs. Converging clinical and preclinical observations implicate pathologies within the corticolimbic glutamate system in the genetic predisposition to, and the development of, an addicted phenotype. Such observations pose cellular factors regulating glutamate transmission as likely molecular candidates in the etiology of addiction. Members of the Homer family of proteins regulate signal transduction through, and the trafficking of, glutamate receptors, as well as maintain and regulate extracellular glutamate levels in corticolimbic brain regions. This review summarizes the existing data implicating the Homer family of protein in acute behavioral and neurochemical sensitivity to drugs of abuse, the development of drug-induced neuroplasticity, as well as other behavioral and cognitive pathologies associated with an addicted state.

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Cloning and Characterization of Postsynaptic Density 93, a Nitric Oxide Synthase Interacting Protein

Cited by 313 publications

References 35 publications

Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma

Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

Homers regulate drug-induced neuroplasticity: Implications for addiction

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