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Mol Cell Proteomics DOI:10.1074/mcp.TIR118.000943

A Curated Resource for Phosphosite-specific Signature Analysis.

Publication TypeJournal Article
Year of Publication2019
AuthorsKrug, K, Mertins, P, Zhang, B, Hornbeck, P, Raju, R, Ahmad, R, Szucs, M, Mundt, F, Forestier, D, Jané-Valbuena, J, Keshishian, H, Gillette, MA, Tamayo, P, Mesirov, JP, Jaffe, JD, Carr, SA, Mani, DR
JournalMol Cell Proteomics
Volume18
Issue3
Pages576-593
Date Published2019 Mar
ISSN1535-9484
Abstract

Signaling pathways are orchestrated by post-translational modifications (PTMs) such as phosphorylation. However, pathway analysis of PTM data sets generated by mass spectrometry (MS)-based proteomics is typically performed at a gene-centric level because of the lack of appropriately curated PTM signature databases and bioinformatic tools that leverage PTM site-specific information. Here we present the first version of PTMsigDB, a database of modification site-specific signatures of perturbations, kinase activities and signaling pathways curated from more than 2,500 publications. We adapted the widely used single sample Gene Set Enrichment Analysis approach to utilize PTMsigDB, enabling ignature nrichment nalysis (PTM-SEA) of quantitative MS data. We used a well-characterized data set of epidermal growth factor (EGF)-perturbed cancer cells to evaluate our approach and demonstrated better representation of signaling events compared with gene-centric methods. We then applied PTM-SEA to analyze the phosphoproteomes of cancer cells treated with cell-cycle inhibitors and detected mechanism-of-action specific signatures of cell cycle kinases. We also applied our methods to analyze the phosphoproteomes of PI3K-inhibited human breast cancer cells and detected signatures of compounds inhibiting PI3K as well as targets downstream of PI3K (AKT, MAPK/ERK) covering a substantial fraction of the PI3K pathway. PTMsigDB and PTM-SEA can be freely accessed at https://github.com/broadinstitute/ssGSEA2.0.

DOI10.1074/mcp.TIR118.000943
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30563849?dopt=Abstract

Alternate JournalMol. Cell Proteomics
PubMed ID30563849
PubMed Central IDPMC6398202
Grant ListU24 CA210986 / CA / NCI NIH HHS / United States
U24 CA194107 / CA / NCI NIH HHS / United States
U24 CA220341 / CA / NCI NIH HHS / United States
U24 CA210979 / CA / NCI NIH HHS / United States
U01 CA214125 / CA / NCI NIH HHS / United States
R01 CA121941 / CA / NCI NIH HHS / United States
U01 CA217885 / CA / NCI NIH HHS / United States