The human DEPhOsphorylation database DEPOD: a 2015 update

Duan, Guangyou; Li, Xun; Köhn, Maja

doi:10.1093/nar/gku1009

Cited by 65 publications

(68 citation statements)

References 33 publications

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“…To evaluate the success of our profiling approach, we compared the list of proteins that were hyperphosphorylated in the ptp‐3 mutant with C. elegans orthologs of previously described substrates of the LAR family. We chose to use the substrates of the LAR family members in the human dephosphorylation database DEPOD (Duan et al., 2015) because currently there are no databases listing dephosphorylation events in C. elegans, there is no entry for ptp‐3 in the Worm Interactome Database (Simonis et al., 2009), and we are unable to find known substrates of ptp‐3 in the literature through PubMed searches.…”

Section: Resultsmentioning

confidence: 99%

Unbiased identification of substrates of protein tyrosine phosphatase ptp‐3 in C. elegans

et al. 2016

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A B S T R A C TThe leukocyte antigen related (LAR) family of receptor-like protein tyrosine phosphatases has three members in humans e PTPRF, PTPRD and PTPRS e that have been implicated in diverse processes including embryonic development, inhibition of cell growth and axonal guidance. Mutations in the LAR family are associated with developmental defects such as cleft palate as well as various cancers including breast, neck, lung, colon and brain. Although this family of tyrosine phosphatases is important for many developmental processes, little is known of their substrates. This is partially due to functional redundancy within the LAR family, as deletion of a single gene in the LAR family does not have an appreciable phenotype, but a dual knockout is embryonically lethal in mouse models. To circumvent the inability to knockout multiple members of the LAR family in mouse models, we used a knockout of ptp-3, which is the only known ortholog of the LAR family in Caenorhabditis elegans and allows for the study of the LAR family at the organismal level. Using SILAC-based quantitative phosphoproteomics, we identified 255 putative substrates of ptp-3, which included four of the nine known annotated substrates of the LAR family. A motif analysis of the identified phosphopeptides allowed for the determination of sequences that appear to be preferentially dephosphorylated. Finally, we discovered that kinases were overrepresented in the list of identified putative substrates and tyrosine residues whose phosphorylation is known to increase kinase activity were dephosphorylated by ptp-3. These data are suggestive of ptp-3 as a potential negative regulator of several kinase families, such as the mitogen activated kinases (MAPKs), and multiple tyrosine kinases including FER, MET, and NTRK2.

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Section: Resultsmentioning

confidence: 99%

Unbiased identification of substrates of protein tyrosine phosphatase ptp‐3 in C. elegans

et al. 2016

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“…Integrating the functional impact of phosphorylation site mutations using high-throughput phenotyping assays with our present analysis framework will be one promising direction for our next-step work (47). In addition to phosphorylation signaling, dephosphorylation signaling by phosphatases also play critical roles in various diseases, such as cancer (48). In our future work, we will investigate both phosphorylation signaling by kinases and dephosphorylation signaling by phosphatases altered by somatic mutations, which may medicate tumorigenesis and anticancer drug responses.…”

Section: Disscussionmentioning

confidence: 99%

Tissue-Specific Signaling Networks Rewired by Major Somatic Mutations in Human Cancer Revealed by Proteome-Wide Discovery

2017

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Massive somatic mutations discovered by large cancer genome sequencing projects provide unprecedented opportunities in the development of precision oncology. However, deep understanding of functional consequences of somatic mutations and identifying actionable mutations and the related drug responses currently remain formidable challenges. Dysfunction of protein post-translational modification plays critical roles in tumorigenesis and drug responses. In this study, we proposed a novel computational oncoproteomics approach, named kinome-wide network module for cancer pharmacogenomics (KNMPx), for identifying actionable mutations that rewired signaling networks and further characterized tumorigenesis and anticancer drug responses. Specifically, we integrated 746,631 missense mutations in 4,997 tumor samples across 16 major cancer types/subtypes from The Cancer Genome Atlas into over 170,000 carefully curated non-redundant phosphorylation sites covering 18,610 proteins. We found 47 mutated proteins (e.g., ERBB2, TP53, and CTNNB1) that had enriched missense mutations at their phosphorylation sites in pan-cancer analysis. In addition, tissue-specific kinase-substrate interaction modules altered by somatic mutations identified by KNMPx were significantly associated with patient survival. We further reported a kinome-wide landscape of pharmacogenomic interactions by incorporating somatic mutation-rewired signaling networks in 1,001 cancer cell lines via KNMPx. Interestingly, we found that cell lines could highly reproduce oncogenic phosphorylation site mutations identified in primary tumors, supporting the confidence in their associations with sensitivity/resistance of inhibitors targeting EGF, MAPK, PI3K, mTOR, and Wnt signaling pathways. In summary, our KNMPx approach is powerful for identifying oncogenic alterations via rewiring phosphorylation-related signaling networks and drug sensitivity/resistance in the era of precision oncology.

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“…Genes were assigned to different classes using publicly available databases for protein kinases (29), protein phosphatases (30), transcription factors (31, 32), and enzymes belonging to the ubiquitin and ubiquitin-like conjugation systems (33). GO annotations containing “calcium” or “calmodulin” within the term definition were employed for selecting calcium and calmodulin–dependent proteins.…”

Section: Methodsmentioning

confidence: 99%

Ouabain‐regulated phosphoproteome reveals molecular mechanisms for Na ⁺ , K ⁺ ‐ATPase control of cell adhesion, proliferation, and survival

et al. 2019

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Ouabain is a cardiotonic steroid with a history of medical uses. It acts as a ligand to the ubiquitous ion pump Na+,K+‐ATPase which it inhibits at high concentrations. At lower concentrations it triggers calcium oscillations and activation of MAP kinases, stimulates cell proliferation as well as adhesion and acts anti‐apoptotic. In light of this, it has been proposed that the pump may have a dual function as a signaling transducer. To investigate this, we have analyzed the phosphoproteome of COS‐7 kidney cells after treatment with sub‐saturating levels (100 nM) of ouabain, which were high enough to induce Ca2+ oscillations but below those needed to modulate the ion pumping function of Na+,K+‐ATPase. Gene ontology analysis was performed to find distinct cellular processes regulated by ouabain after 10 and 20 min of treatment in the phopshoproteomic analysis. The analysis revealed 2580 ouabain‐regulated phosphorylation sites, many of which were associated with cell adhesion and proliferation. Two of the regulated phospho‐proteins were the inositol triphosphoate receptor (InsP3) and stromal interaction molecule (STIM), both of which are essential for ouabain‐induced calcium oscillations. We used siRNA and Western blotting for target confirmation. One confirmed target, calcium/calmodulin‐dependent protein kinase II gamma (CAMK2γ), were shown to be involved in the anti‐apoptotic effect of ouabain; siRNA silencing of CaMK2γ in primary renal cells eliminates the protective effect of ouabain against apoptosis induced by either serum starvation or glucose. In conclusion, our findings support a role for Na+,K+‐ATPase as a signal transducer that serves to protect cell and tissue integrity. Support or Funding Information This study was supported by the Swedish Research Council and Erling‐Persson Family Foundation. D.S. is supported by a Novo Nordisk postdoctoral fellowship run in partnership with Karolinska Institutet. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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The human DEPhOsphorylation database DEPOD: a 2015 update

Cited by 65 publications

References 33 publications

Unbiased identification of substrates of protein tyrosine phosphatase ptp‐3 in C. elegans

Unbiased identification of substrates of protein tyrosine phosphatase ptp‐3 in C. elegans

Tissue-Specific Signaling Networks Rewired by Major Somatic Mutations in Human Cancer Revealed by Proteome-Wide Discovery

Ouabain‐regulated phosphoproteome reveals molecular mechanisms for Na ⁺ , K ⁺ ‐ATPase control of cell adhesion, proliferation, and survival

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The human DEPhOsphorylation database DEPOD: a 2015 update

Cited by 65 publications

References 33 publications

Unbiased identification of substrates of protein tyrosine phosphatase ptp‐3 in C. elegans

Unbiased identification of substrates of protein tyrosine phosphatase ptp‐3 in C. elegans

Tissue-Specific Signaling Networks Rewired by Major Somatic Mutations in Human Cancer Revealed by Proteome-Wide Discovery

Ouabain‐regulated phosphoproteome reveals molecular mechanisms for Na + , K + ‐ATPase control of cell adhesion, proliferation, and survival

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Ouabain‐regulated phosphoproteome reveals molecular mechanisms for Na ⁺ , K ⁺ ‐ATPase control of cell adhesion, proliferation, and survival