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Abstract
Constitutive activity of kinases is known to be crucial for a tumor to maintain its malignant phenotype, a phenomenon which is often referred to as oncogene addiction. The in-depth analysis of aberrant signaling pathways by the analysis of protein phosphorylation has become feasible through recent advances in proteomics technology. In this article we will review developments in the field of phosphoproteomics and its application in cancer research. The most widely used technologies for the generic enrichment of phosphopeptides are discussed as well as targeted approaches for the analysis of a specific subset of phosphopeptides. Validation experiments of phosphorylation sites using targeted mass spectrometry are also explained. Finally, we will highlight applications of phosphoproteomic technology in cancer research using cell lines and tissue.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
The current generic phosphopeptide enrichment methods purify 10,000s of phosphopeptides but are not comprehensive yet.
Motif-specific antibodies and phosphotyrosine antibodies are used to enrich low abundant signaling peptides.
Selected ion monitoring/multiple reaction monitoring-based methods can contribute to the validation and quantification of phosphorylation sites in clinical settings and may make the use of antibody-based validation experiments obsolete in the future.
One-shot phosphopeptide enrichment and analysis approaches show great promise in the field of label-free proteomics due to increased throughput and reproducibility.
Due to its unbiased nature and an ever increasing arsenal of kinase inhibitors approaching US FDA approval, phosphoproteomics will gain importance in the field of drug resistance research.
Molecular signatures based on pathway activation will refine existing tumor subtypes and support patient-tailored therapy.
