Modified Pathways: Integration of manually curated pathways and high throughput protein phosphorylation data
Post-translational modification of proteins is an important mechanism used by the cell in the control of metabolism, so errors in one of these modification processes can have profound effects on the cell. In particular, post-translational phosphorylation is a central mechanism in cell signalling, making the understanding of the role of phosphorylation in health and disease a crucial challenge. Aberrant signalling is almost always implicated in cancer.
In studies of post-translational phosphorylation individual proteins of interest have been tested using biochemical methods, and the results reported in the literature. More recently, developments in mass spectrometry have made it possible to rapidly detect thousands of phosphorylation sites in a sample. These data are made available in a dedicated resource.
Integration of data sources is an important on-going issue in bioinformatics. In this project the student used skills developed through the course modules to enable integration of three important datatypes; pathway data, proteomics data and details of somatic mutations in cancer. The use of the new tool is illustrated using Wnt signalling as an example.
Reactome, PRIDE and COSMIC
Reactome is a pathway database. The data, including the details of protein phosphorylation, are obtained from the literature and are checked by an expert curator.
The PRoteomics IDEntifications (PRIDE) database holds data on proteins and peptides, including details of post-translational modifications.
The COSMIC database is a Catalogue Of Somatic Mutations In Cancer. The data are obtained from the literature and from sample screening.
By enabling the integration of data from these resources this project has provided an easy method for the user to discover whether a protein with a known post-translational modification has been implicated in cancer.
Wnt signalling and cancer mutations
The activation of the canonical Wnt pathway leads to the transcription of Wnt-regulated genes; errors in Wnt signalling can play a role in carcinogenesis. Beta-catenin is a key component of this pathway, and the COSMIC database contains many examples of mutations in the gene in samples from cancers. By linking information on protein modifications with the cancer mutations, it is possible to show that the residues that would normally have been phosphorylated have been lost.
Critical amino acid residues in proteins: a BioMart integration of Reactome protein annotations with PRIDE mass spectrometry data and COSMIC somatic mutations
Nelson Ndegwa, Richard G. Côté, David Ovelleiro, Peter D'Eustachio, Henning Hermjakob, Juan A. Vizcaíno and David Croft
The Reactome BioMart
Robin A. Haw, David Croft, Christina K. Yung, Nelson Ndegwa, Peter D'Eustachio, Henning Hermjakob and Lincoln D. Stein