Computational methods and opportunities for phosphorylation network medicine

Protein phosphorylation, one of the most ubiquitous post-translational modifications (PTM) of proteins, is known to play an essential role in cell signaling and regulation. With the increasing understanding of the complexity and redundancy of cell signaling, there is a growing recognition that targeting the entire network or system could be a necessary and advantageous strategy for treating cancer. Protein kinases, the proteins that add a phosphate group to the substrate proteins during phosphorylation events, have become one of the largest groups of 'druggable' targets in cancer therapeutics in recent years. Kinase inhibitors are being regularly used in clinics for cancer treatment. This therapeutic paradigm shift in cancer research is partly due to the generation and availability of high-dimensional proteomics data. Generation of this data, in turn, is enabled by increased use of mass-spectrometry (MS)-based or other high-throughput proteomics platforms as well as companion public databases and computational tools. This review briefly summarizes the current state and progress on phosphoproteomics identification, quantification, and platform related characteristics. We review existing database resources, computational tools, methods for phosphorylation network inference, and ultimately demonstrate the connection to therapeutics. Finally, many research opportunities exist for bioinformaticians or biostatisticians based on developments and limitations of the current and emerging technologies.