NetPath: a public resource of curated signal transduction pathways

Kandasamy, Kumaran; Mohan, S. Sujatha; Raju, Rajesh; Keerthikumar, Shivakumar; Kumar, Gaurav; Venugopal, Abhilash; Telikicherla, Deepthi; Navarro, Daniel J.; Mathivanan, Suresh; Pecquet, Christian; Gollapudi, Sashi Kanth; Tattikota, Sudhir Gopal; Padhukasahasram, Hariprasad; Subbannayya, Yashwanth; Goel, Renu; Jacob, Harrys K.C.; Zhong, Jun; Sekhar, Raja; Nanjappa, Vishalakshi; Balakrishnan, Lavanya; Subbaiah, Roopashree; Ramachandra, Y. L.; Rahiman, B. Abdul; Prasad, T. S. Keshava; Lin, Juntang; Houtman, Jon C. D.; Desiderio, Stephen; Renauld, Jean‐Christophe; Constantinescu, Stefan N.; Ohara, Osamu; Hirano, Toshio; Kubo, Masato; Singh, Sujay; Khatri, Purvesh; Drăghici, Sorin; Bader, Gary D.; Sander, Chris; Leonard, Warren J.; Pandey, Akhilesh

doi:10.1186/gb-2010-11-1-r3

Cited by 466 publications

(446 citation statements)

References 43 publications

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“…gov), the Interactome (www.ebi.ac.uk/intact/), and the Molecular Interaction Database (http://mint.bio.uniroma2.it/mint/). Protein interactions in this network include physical stable interactions such as those defining protein complexes, as well as transient interactions such as posttranslational modifications and enzymatic reactions found in signal transduction pathways, including 20 highly curated immune and cancer signaling pathways from NetPath (www.netpath.org) (56). We focused on nonredundant interactions, only included nodes with an Entrez gene ID annotation, and focused on the maximally connected component.…”

Section: Methodsmentioning

confidence: 99%

Distinctive topology of age-associated epigenetic drift in the human interactome

West

Widschwendter

Teschendorff

2013

Proc. Natl. Acad. Sci. U.S.A.

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Recently, it has been demonstrated that DNA methylation, a covalent modification of DNA that can regulate gene expression, is modified as a function of age. However, the biological and clinical significance of this age-associated epigenetic drift is unclear. To shed light on the potential biological significance, we here adopt a systems approach and study the genes undergoing age-associated changes in DNA methylation in the context of a protein interaction network, focusing on their topological properties. In contrast to what has been observed for other age-related gene classes, including longevity-and disease-associated genes, as well as genes undergoing age-associated changes in gene expression, we here demonstrate that age-associated epigenetic drift occurs preferentially in genes that occupy peripheral network positions of exceptionally low connectivity. In addition, we show that these genes synergize topologically with disease and longevity genes, forming unexpectedly large network communities. Thus, these results point toward a potentially distinct mechanistic and biological role of DNA methylation in dictating the complex aging and disease phenotypes.biological networks | epigenomics | aging | network topology

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Section: Methodsmentioning

confidence: 99%

Distinctive topology of age-associated epigenetic drift in the human interactome

West

Widschwendter

Teschendorff

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…PPI networks were annotated, visualized, and analyzed with NAViGaTOR v2.1.14 (36) (the complete method is described in SI Materials and Methods). Transcriptional targets of the TGF-β signaling pathway were annotated as per NetPath and specific literature (16,17).…”

Section: Methodsmentioning

confidence: 99%

“…The proteins in this network are also enrichment for genes/proteins in the KEGG pathway of ECM-receptor interaction (P = 0.021) and GO biological process of cell migration (P = 0.034). Importantly, 7 of the 14 overlap genes were reported as transcriptional targets of the TGF-β signaling pathway (NetPath) (16,17). These included ITGA11 (18,19), MFAP5 (MAGP-2/MP-25) (20), THBS2 (21), A2M (22), CLU (23), CTHRC1 (24), and SULF1 (17).…”

Section: Shared Differentially Expressed Genes Of Caf and Tumor Stromamentioning

confidence: 99%

Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer

Navab

Strumpf

Bandarchi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

321

302

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The tumor microenvironment strongly influences cancer development, progression, and metastasis. The role of carcinoma-associated fibroblasts (CAFs) in these processes and their clinical impact has not been studied systematically in non-small cell lung carcinoma (NSCLC). We established primary cultures of CAFs and matched normal fibroblasts (NFs) from 15 resected NSCLC. We demonstrate that CAFs have greater ability than NFs to enhance the tumorigenicity of lung cancer cell lines. Microarray gene-expression analysis of the 15 matched CAF and NF cell lines identified 46 differentially expressed genes, encoding for proteins that are significantly enriched for extracellular proteins regulated by the TGF-β signaling pathway. We have identified a subset of 11 genes (13 probe sets) that formed a prognostic gene-expression signature, which was validated in multiple independent NSCLC microarray datasets. Functional annotation using protein-protein interaction analyses of these and published cancer stroma-associated gene-expression changes revealed prominent involvement of the focal adhesion and MAPK signaling pathways. Fourteen (30%) of the 46 genes also were differentially expressed in laser-capture-microdissected corresponding primary tumor stroma compared with the matched normal lung. Six of these 14 genes could be induced by TGF-β1 in NF. The results establish the prognostic impact of CAF-associated gene-expression changes in NSCLC patients.integrin α11 | NAViGaTOR | adenocarcinoma | extracellular matrix

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“…Taken together, our data greatly expand the understanding of the TSLP signaling pathway by discovering 226 TSLP-regulated phosphoproteins. These TSLP-regulated phosphoproteins have already been uploaded to a publicly available pathway resource NetPath (http://www.NetPath.org) (96).…”

Section: Btk Protein Tyrosine Kinasementioning

confidence: 99%

TSLP Signaling Network Revealed by SILAC-Based Phosphoproteomics

Zhong

Kim

Chaerkady³

et al. 2012

Molecular & Cellular Proteomics

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Thymic stromal lymphopoietin (TSLP) is a cytokine that plays diverse roles in the regulation of immune responses. TSLP requires a heterodimeric receptor complex consisting of IL-7 receptor ␣ subunit and its unique TSLP receptor (gene symbol CRLF2) to transmit signals in cells. Abnormal TSLP signaling (e.g. overexpression of TSLP or its unique receptor TSLPR) contributes to the development of a number of diseases including asthma and leukemia. However, a detailed understanding of the signaling pathways activated by TSLP remains elusive. In this study, we performed a global quantitative phosphoproteomic analysis of the TSLP signaling network using stable isotope labeling by amino acids in cell culture. By employing titanium dioxide in addition to antiphosphotyrosine antibodies as enrichment methods, we identified 4164 phosphopeptides on 1670 phosphoproteins. Using stable isotope labeling by amino acids in cell culture-based quantitation, we determined that the phosphorylation status of 226 proteins was modulated by TSLP stimulation. Our analysis identified activation of several members of the Src and Tec families of kinases including Btk, Lyn, and Tec by TSLP for the first time. In addition, we report TSLP-induced phosphorylation of protein phosphatases such as Ptpn6 (SHP-1) and Ptpn11 (Shp2), which has also not been reported previously. Co-immunoprecipitation assays showed that Shp2 binds to the adapter protein Gab2 in a TSLP-dependent manner. This is the first demonstration of an inducible protein complex in TSLP signaling. A kinase inhibitor screen revealed that pharmacological inhibition of PI-3 kinase, Jak family kinases, Src family kinases or Btk suppressed TSLP-dependent cellular proliferation making them candidate therapeutic targets in diseases resulting from aberrant TSLP signaling. Our study is the first phosphoproteomic analysis of the TSLP signaling pathway that greatly expands our understanding of TSLP signaling and provides novel therapeutic targets for TSLP/ TSLPR-associated diseases in humans. Molecular & Cellular Proteomics 11: 10.1074/mcp.M112.017764, 1-22, 2012. Thymic stromal lymphopoietin (TSLP)1 is an IL-7-like fourhelix bundle cytokine that was originally identified as a growth factor from the conditioned medium of the Z210R.1 thymic stromal cell line to support B-cell development in the absence of IL-7 (1, 2). TSLP mediates its effects through a heterodimeric receptor complex consisting of IL-7R␣ and a unique TSLP receptor (TSLPR, also known as CRLF2) (3, 4). In humans, epithelial cells are the major source of TSLP (5), which acts on a number of distinctive cell types. TSLP released from airway epithelial cells synergizes with IL-1 and TNF to stimulate the production of high levels of Th2 cytokines by mast cells (6). TSLP can promote the maturation of dendritic cells, thereby driving the Type 2 differentiation of T helper cells (7). Studies have also shown that TSLP enhances proliferation of CD4ϩ and CD8ϩ T cells activated by T-cell receptor stimulation (8, 9). In mice, TSLP can also activ...

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NetPath: a public resource of curated signal transduction pathways

Abstract: NetPath, a novel community resource of curated human signaling pathways is presented and its utility demonstrated using immune signaling data.

Cited by 466 publications

References 43 publications

Distinctive topology of age-associated epigenetic drift in the human interactome

Distinctive topology of age-associated epigenetic drift in the human interactome

Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer

TSLP Signaling Network Revealed by SILAC-Based Phosphoproteomics

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