High-Throughput Mapping of a Dynamic Signaling Network in Mammalian Cells

Barrios‐Rodiles, Miriam; Brown, Kevin R.; Ozdamar, Barish; Bose, Rohit; Liu, Zhong; Donovan, Robert S.; Shinjo, Fukiko; Liu, Yongmei; Dembowy, Joanna; Taylor, Ian W.; Luga, Valbona; Pržulj, Nataša; Robinson, Mark D.; Suzuki, Harukazu; Hayashizaki, Yoshihide; Jurišica, Igor; Wrana, Jeffrey L.

doi:10.1126/science.1105776

Cited by 650 publications

(565 citation statements)

References 21 publications

Supporting

Mentioning

547

Contrasting

Unclassified

Order By: Relevance

“…The results revealed a significantly higher signal for SNAP-25 and PSD-95 compared with PSD-95 and the merely presynaptic protein Piccolo (Figures 5a and b), suggesting that PSD-95 and SNAP-25 can be part of the same complex in their natural cellular environment. To further probe the possible existence of a postsynaptic protein network including SNAP-25, we applied a LUminescence-based Mammalian intERactome (LUMIER) assay 39,40 to test the following protein-protein interactions: SNAP-25 and PSD-95; PSD-95 and p140Cap (SRCIN1). The rationale for including p140Cap in the assay results from our previous demonstration that acute downregulation of SNAP-25 impairs spines morphogenesis through p140Cap, 23 a synaptic protein involved in Src-kinase regulation and microtubules organization inside the spine.…”

Section: Resultsmentioning

confidence: 99%

Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis

et al. 2015

View full text Add to dashboard Cite

Impairment of synaptic function can lead to neuropsychiatric disorders collectively referred to as synaptopathies. The SNARE protein SNAP-25 is implicated in several brain pathologies and, indeed, brain areas of psychiatric patients often display reduced SNAP-25 expression. It has been recently found that acute downregulation of SNAP-25 in brain slices impairs long-term potentiation; however, the processes through which this occurs are still poorly defined. We show that in vivo acute downregulation of SNAP-25 in CA1 hippocampal region affects spine number. Consistently, hippocampal neurons from SNAP-25 heterozygous mice show reduced densities of dendritic spines and defective PSD-95 dynamics. Finally, we show that, in brain, SNAP-25 is part of a molecular complex including PSD-95 and p140Cap, with p140Cap being capable to bind to both SNAP-25 and PSD-95. These data demonstrate an unexpected role of SNAP-25 in controlling PSD-95 clustering and open the possibility that genetic reductions of the protein levels -as occurring in schizophrenia -may contribute to the pathology through an effect on postsynaptic function and plasticity. Cell Death and Differentiation (2015) 22, 1425-1436 doi:10.1038/cdd.2014 published online 13 February 2015 Synapses are complex cellular junctions specialized for communication between neurons. Epidemiological and genetic studies demonstrated that deficiencies in synapse function 1 are implicated in a wide range of brain disorders, including neurodegenerative 2 and psychiatric diseases such as schizophrenia 3,4 and autism. 5,6 A hallmark of synaptic specializations is their dependence on highly organized complexes of proteins that interact with each other. Therefore, the loss or modification of key synaptic proteins might directly affect the properties of such networks and, ultimately, synaptic function.SNAP-25 is a component of the SNARE complex, which is central to synaptic vesicle exocytosis 7,8 and which has a role in the regulation of voltage-gated calcium channels. 9,10 The SNAP25 gene has been associated with attention deficit hyperactivity disorder (ADHD) 11,12 and with schizophrenia. 13,14 Consistently, SNAP-25 levels are lower in the hippocampus 15 and in the frontal lobe 16 of patients with schizophrenia. DNA variants of the SNAP25 gene that associate with ADHD are also associated with reduced expression level of the transcript in prefrontal cortex. 17 Finally, reduction of SNAP-25 levels has been found to cause neurodegeneration in mice lacking the synaptic vesicle protein Cysteine-string protein-α, possibly due to the impaired SNARE-complex assembly produced by the decreased SNAP-25. 18 The mechanisms by which reduced SNAP-25 expression may result in a psychiatric disease are still undefined, although alterations in neurotransmitter release have been indicated as potential causative processes. 19,20 Recently an unexpected postsynaptic role of SNAP-25 has been described, with the protein controlling NMDA and kainate receptor trafficking. 21 Furthermore, it has been lately ...

show abstract

Section: Resultsmentioning

confidence: 99%

Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Occludin has also been linked to the regulation of various subcellular signalling pathways, such as MAP-kinase-dependent pathways and RhoA signalling. In the case of the regulation of Raf1 and TGFβ, this signalling function involves the second (more C-terminal) extracellular domain (Barrios-Rodiles et al, 2005;Wang et al, 2005;Yu et al, 2005). However, the underlying molecular mechanisms of many of the processes to which occludin has been linked remain to be determined and the functional relevance of most of its biochemical interactions is still unknown.…”

Section: Occludinmentioning

confidence: 99%

Tight junctions at a glance

Balda

Matter

2008

Journal of Cell Science

208

168

View full text Add to dashboard Cite

“…The TBL2 protein has a single transmembrane domain, five WD40 domains, and a putative nuclear localization signal. A role for TBL2 in TGFb signaling was suggested via interaction with the SMURF1 ubiquitin ligase (Barrios-Rodiles et al, 2005). TBL2 was also found to undergo phosphorylation at T433 by ATM/ATR in response to oxidative DNA damage (Matsuoka et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

Fredericks

McGarvey

Wang

et al. 2011

DNA and Cell Biology

View full text Add to dashboard Cite

Convergent evidence implicates the TERE1 protein in human bladder tumor progression and lipid metabolism. Previously, reduced TERE1 expression was found in invasive urologic cancers and inhibited cell growth upon re-expression. A role in lipid metabolism was suggested by TERE1 binding to APOE, a cholesterol carrier, and to TBL2, a candidate protein in triglyceride disorders. Natural TERE1 mutations associate with Schnyder's corneal dystrophy, characterized by lipid accumulation. TERE1 catalyzes menaquinone synthesis, known to affect cholesterol homeostasis. To explore this relationship, we altered TERE1 and TBL2 dosage via ectopic expression and interfering RNA and measured cholesterol by Amplex red. Protein interactions of wild-type and mutant TERE1 with GST-APOE were evaluated by binding assays and molecular modeling. We conducted a bladder tumor microarray TERE1 expression analysis and assayed tumorigenicity of J82 cells ectopically expressing TERE1. TERE1 expression was reduced in a third of invasive specimens. Ectopic TERE1 expression in J82 bladder cancer cells dramatically inhibited nude mouse tumorigenesis. TERE1 and TBL2 proteins inversely modulated cellular cholesterol in HEK293 and bladder cancer cells from 20% to 50%. TERE1 point mutations affected APOE interactions, and resulted in cholesterol levels that differed from wild type. Elevated tumor cell cholesterol is known to affect apoptosis and growth signaling; thus, loss of TERE1 in invasive bladder cancer may represent a defect in menaquinone-mediated cholesterol homeostasis that contributes to progression.

show abstract

High-Throughput Mapping of a Dynamic Signaling Network in Mammalian Cells

Cited by 650 publications

References 21 publications

Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis

Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis

Tight junctions at a glance

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

Contact Info

Product

Resources

About