In silico prediction of physical protein interactions and characterization of interactome orphans

Kotlyar, Max; Pastrello, Chiara; Pivetta, Flavia; Sardo, Alessandra Lo; Cumbaa, Christian; Li, Han; Naranian, Taline; Niu, Yun; Ding, Zhiyong; Vafaee, Fatemeh; Broackes-Carter, Fiona; Petschnigg, Julia; Mills, Gordon B.; Jurisicova, Andrea; Štagljar, Igor; Maestro, Roberta; Jurišica, Igor

doi:10.1038/nmeth.3178

Cited by 147 publications

(138 citation statements)

References 48 publications

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“…pathDIP provides literature-driven and computationally predicted annotations for known membership and significant association of genes to molecular pathways. It integrates data that originate from multiple resources for molecular pathway annotations (34) and protein-protein interactions (35,36). This analysis identified 968 significantly enriched pathways (P < 0.01; list in Supplementary Table S2).…”

Section: Resultsmentioning

confidence: 99%

Uninterrupted Sedentary Behavior Downregulates BRCA1 Gene Expression

Pettapiece-Phillips

Kotlyar

Chehade

et al. 2016

Cancer Prevention Research

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BRCA1 mutation carriers face a high lifetime risk of developing breast cancer. Physical activity induces broad transcriptional changes, and multiple studies have documented its beneficial effects across cancers. Because haploinsufficiency predisposes to breast cancer in these women, factors that increase BRCA1 levels may mitigate the effect of the mutation. Whether physical activity modulates BRCA1 expression and whether lifestyle factors could benefit women with a mutation remain unclear. The objective of this study was to systematically evaluate whether physical activity or sedentary behavior affects BRCA1 mRNA expression. Activity levels were assessed in 50 female participants (14 BRCA1 mutation carriers and 36 noncarriers) using the GT3X Actigraph accelerometer, and BRCA1 mRNA expression was quantified from peripheral blood lymphocytes using the Nanostring nCounter Analysis System. There was a significant negative correlation between the longest sedentary bout and BRCA1 mRNA expression (r ¼ -0.32; P ¼ 0.02). Women below the median for the longest sedentary bout had significantly higher BRCA1 mRNA levels compared with women above the median (161 vs. 132 counts; P ¼ 0.04; one-sided Mann-Whitney U test). There was no significant relationship between mean metabolic equivalents of task rate or mean sedentary time and BRCA1 mRNA expression (Spearman correlation P ! 0.75; P ! 0.14; Mann-Whitney U test). These findings suggest that prolonged periods of sedentary behavior are associated with significantly lower BRCA1 mRNA expression. Whether this translates into a potentially more harmful effect in BRCA1 mutation carriers warrants further investigation. Cancer Prev Res; 9(1); 83-88. Ó2015 AACR.

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Section: Resultsmentioning

confidence: 99%

Uninterrupted Sedentary Behavior Downregulates BRCA1 Gene Expression

Pettapiece-Phillips

Kotlyar

Chehade

et al. 2016

Cancer Prevention Research

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“…This approach has some important limitations. For example, there may be a high false positive rate for predictive modeling in humans because interactomes are defined in the absence of specific cell contexts (64), in which putative protein partners may not be co-expressed. Yeast-two hybrid discovery screens identify protein-protein interactions and map putative interactome networks (15, 16), but this approach does not address cell context limitations of interactions.…”

Section: Discussionmentioning

confidence: 99%

Receptor Tyrosine Kinase MET Interactome and Neurodevelopmental Disorder Partners at the Developing Synapse

Baker

Eagleson

et al. 2016

Biological Psychiatry

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Background Atypical synapse development and plasticity are implicated in many neurodevelopmental disorders (NDDs). NDD-associated, high confidence risk genes have been identified, yet little is known about functional relationships at the level of protein-protein interactions, which are the dominant molecular bases responsible for mediating circuit development. Methods Proteomics in three independent developing neocortical synaptosomal preparations identified putative interacting proteins of the ligand-activated MET receptor tyrosine kinase, an autism risk gene that mediates synapse development. The candidates were translated into interactome networks and analyzed bioinformatically. Additionally, three independent quantitative proximity ligation assays (PLA) in cultured neurons and four independent immunoprecipitation analyses of synaptosomes validated protein interactions. Results Approximately 11% (8/72) of MET-interacting proteins, including SHANK3, SYNGAP1 and GRIN2B, are associated with NDDs. Proteins in the MET interactome were translated into a novel MET interactome network based on human protein-protein interaction databases. High confidence genes from different NDD datasets that encode synaptosomal proteins were analyzed for being enriched in MET interactome proteins. This was found for autism, but not schizophrenia, bipolar disorder, major depressive disorder or attentional deficit hyperactivity disorder. There is correlated gene expression between MET and its interactive partners in developing human temporal and visual neocortices, but not with highly expressed genes that are not in the interactome. PLA and biochemical analyses demonstrate that MET-protein partner interactions are dynamically regulated by receptor activation. Conclusions The results provide a novel molecular framework for deciphering the functional relations of key regulators of synaptogenesis that contribute to both typical cortical development and to NDDs.

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“…Chronic exposure to excessive nutritional lipids is known to trigger inflammatory-like response in the brain that are partially mediated by NF-κB , which n turn, acts a direct and indirect transcriptional regulator of DA receptor abundance and signaling. Accordingly, in silico analysis of the possible human protein-protein interactions reveals that among the ~30 predicted possible partners for human ANKK1 protein [110] half are found in pathways related to inflammatory responses including the NF-κB, cytokine pathways. Notably, in the brain ANKK1 is highly represented, if not uniquely expressed in astrocytes [111, 112].…”

Section: Taqia Polymorphism (Rs1800497)mentioning

confidence: 99%

DRD2: Bridging the Genome and Ingestive Behavior

Sun

Luquet

2017

Trends in Cognitive Sciences

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Recent work highlights the importance of genetic variants that influence brain structure and function in conferring risk for polygenic obesity. The neurotransmitter dopamine (DA) plays a pivotal role in energy balance by integrating metabolic signals with circuits supporting cognitive, perceptual and appetitive functions that guide feeding. It has also been established that diet and obesity alter DA signaling leading to compulsive-like feeding and neurocognitive impairments. This raises the possibility that genetic variants that influence DA signaling and adaptation confer risk for overeating and cognitive decline. We consider the role of two common gene variants, FTO and TaqIA rs1800497 in driving gene * environment interactions promoting obesity, metabolic dysfunction, and cognitive change via their influence on dopamine receptor subtype 2 signaling.

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In silico prediction of physical protein interactions and characterization of interactome orphans

Cited by 147 publications

References 48 publications

Uninterrupted Sedentary Behavior Downregulates BRCA1 Gene Expression

Uninterrupted Sedentary Behavior Downregulates BRCA1 Gene Expression

Receptor Tyrosine Kinase MET Interactome and Neurodevelopmental Disorder Partners at the Developing Synapse

DRD2: Bridging the Genome and Ingestive Behavior

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