Temporal proteomics of NGF-TrkA signaling identifies an inhibitory role for the E3 ligase Cbl-b in neuroblastoma cell differentiation

Emdal, Kristina B.; Pedersen, Anna-Kathrine; Bekker-Jensen, Dorte B.; Tsafou, Kalliopi; Horn, Heiko; Lindner, Sven; Schulte, Johannes H.; Eggert, Angelika; Jensen, Lars Juhl; Francavilla, Chiara; Olsen, Jesper V.

doi:10.1126/scisignal.2005769

Cited by 67 publications

(68 citation statements)

References 81 publications

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“…Class I phosphopeptide sites comprise those residues with the highest localization probability for the phospho-group (>0.75); that is, the sum of probabilities of other potential sites is less than 0.25. From more than 2,000 identified and quantified class I phospho-sites, the distribution of phosphoserine (pSer), phosphothreonine (pThr), and phosphotyrosine (pTyr) sites observed in cells transfected with rat or chimeric TrkA was similar to distributions reported previously with cells stimulated with NGF or epidermal growth factor (EGF) (Emdal et al., 2015, Olsen et al., 2006). We next examined the NGF-upregulated phospho-sites and found that significantly more phosphopeptides were upregulated in NGF-treated cells with rat TrkA (361/2,239 [16.8%]) compared to cells with chimeric TrkA (270/2,007 [13.5%]; Figure 4B).…”

Section: Resultssupporting

confidence: 80%

Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat

et al. 2016

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SummaryThe naked mole-rat is a subterranean rodent lacking several pain behaviors found in humans, rats, and mice. For example, nerve growth factor (NGF), an important mediator of pain sensitization, fails to produce thermal hyperalgesia in naked mole-rats. The sensitization of capsaicin-sensitive TRPV1 ion channels is necessary for NGF-induced hyperalgesia, but naked mole-rats have fully functional TRPV1 channels. We show that exposing isolated naked mole-rat nociceptors to NGF does not sensitize TRPV1. However, the naked mole-rat NGF receptor TrkA displays a reduced ability to engage signal transduction pathways that sensitize TRPV1. Between one- and three-amino-acid substitutions in the kinase domain of the naked mole-rat TrkA are sufficient to render the receptor hypofunctional, and this is associated with the absence of heat hyperalgesia. Our data suggest that evolution has selected for a TrkA variant that abolishes a robust nociceptive behavior in this species but is still compatible with species fitness.

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Section: Resultssupporting

confidence: 80%

Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat

et al. 2016

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“…The numbers of identified phosphosites were in agreement with previous studies (32,49) and different drug treatments displayed a good reproducibility with a Pearson correlation R in the range of 0.62-0.82 ( Supplementary Fig. S4B and S4C).…”

Section: Quantitative Phosphoproteomics Identifies Functionally Relevsupporting

confidence: 76%

Combinatorial Drug Screening Identifies Ewing Sarcoma–specific Sensitivities

Radic-Sarikas

Tsafou

Emdal

et al. 2017

Molecular Cancer Therapeutics

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Abbreviations: EWS, Ewing sarcoma breakpoint region 1, at chromosome 22; ETS, E-twenty-six family; FLI1, Friend leukemia integration 1 transcription factor; INSR, insulin receptor; IGF1, Insulin-like growth factor 1; IGF1R, insulin-like growth factor 1 receptor; CI, combination index; MS, mass spectrometry; LC-MS, liquid chromatography-mass spectrometry; LC-MS/MS, liquid chromatography-tandem mass spectrometry; kd, knockdown. AbstractImprovements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any associated adverse side effects through reduced dosing, which is particularly important in childhood tumors. Using a parallel phenotypic combinatorial screening approach of cells derived from three pediatric tumor types, we identified Ewing sarcoma -specific interactions of a diverse set of targeted agents including approved drugs. We were able to retrieve highly synergistic drug combinations specific for Ewing sarcoma and identified signaling processes important for Ewing sarcoma cell proliferation determined by EWS-FLI1. We generated a molecular target profile of PKC412, a multikinase inhibitor with strong synergistic propensity in Ewing sarcoma, revealing its targets in critical Ewing sarcoma signaling routes. Using a multilevel experimental approach including quantitative phosphoproteomics, we analyzed the molecular rationale behind the disease-specific synergistic effect of simultaneous application of PKC412 and IGF1R inhibitors. The mechanism of the drug synergy between these inhibitors is different from the sum of the mechanisms of the single agents. The combination effectively inhibited pathway crosstalk and averted feedback loop repression, in EWS-FLI1 dependent manner.3

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“…Using the Cytoscape STRING app, a network was retrieved for 78 proteins interacting with TrkA (tropomyosin-related kinase A) 10 min after stimulating neuroblastoma cells with NGF (nerve growth factor) (56). With a confidence cutoff of 0.4, the resulting network contains 182 functional associations between 57 of the proteins; the 21 proteins with no associations to other proteins in the network were removed.…”

Section: Cytoscape App Integrationmentioning

confidence: 99%

The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible

et al. 2016

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A system-wide understanding of cellular function requires knowledge of all functional interactions between the expressed proteins. The STRING database aims to collect and integrate this information, by consolidating known and predicted protein–protein association data for a large number of organisms. The associations in STRING include direct (physical) interactions, as well as indirect (functional) interactions, as long as both are specific and biologically meaningful. Apart from collecting and reassessing available experimental data on protein–protein interactions, and importing known pathways and protein complexes from curated databases, interaction predictions are derived from the following sources: (i) systematic co-expression analysis, (ii) detection of shared selective signals across genomes, (iii) automated text-mining of the scientific literature and (iv) computational transfer of interaction knowledge between organisms based on gene orthology. In the latest version 10.5 of STRING, the biggest changes are concerned with data dissemination: the web frontend has been completely redesigned to reduce dependency on outdated browser technologies, and the database can now also be queried from inside the popular Cytoscape software framework. Further improvements include automated background analysis of user inputs for functional enrichments, and streamlined download options. The STRING resource is available online, at http://string-db.org/.

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Temporal proteomics of NGF-TrkA signaling identifies an inhibitory role for the E3 ligase Cbl-b in neuroblastoma cell differentiation

Cited by 67 publications

References 81 publications

Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat

Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat

Combinatorial Drug Screening Identifies Ewing Sarcoma–specific Sensitivities

The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible

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