Phosphoproteomics-Based Network Analysis of Cancer Cell Signaling Systems
Signal transduction systems are known to regulate complex biological events such as cell proliferation and differentiation via sequential phosphorylation/dephosphorylation reactions over all cellular networks. Recent technological advances regarding high-resolution mass spectrometry-based quantitative proteomics, in combination with phosphorylation-directed protein/peptide enrichment methodology, have enabled us to grasp the comprehensive status of phosphorylated cellular signaling molecules in a time-resolved manner. Phosphotyrosine-targeted sample enrichment by anti-phosphotyrosine antibodies allows us to describe key regulatory signaling dynamics triggered by tyrosine kinases, including epidermal growth factor receptor, in various contexts of cancer cell signaling. Furthermore, chemistry-based phosphopeptide enrichment technologies such as immobilized metal affinity chromatography and metal oxide chromatography lead us to obtain a serine/threonine/tyrosine-phosphorylation dependent global landscape of cellular signaling at the network level. In this chapter, we introduce recent technological advances regarding phosphoproteomics-based computational analyses of signaling regulation and discuss the future directions of cancer research toward theoretical exploration of drug targets from a system-level point of view.
KeywordsSignal transduction NanoLC-MS/MS Phosphoproteomics Quantitative proteomics Computational modeling Network analysis Systems biology
We gratefully acknowledge our colleagues at Medical Proteomics Laboratory, the Institute of Medical Science, the University of Tokyo for helpful discussions and comments. This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas from Japan Society for the Promotion of Science (JSPS) and The Ministry of Education, Culture, Sports, Science and Technology (MEXT).
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