PhosphoX-db: A web-based bioinformatics platform for studying non-canonical phosphorylation

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The key molecules that mediate cellular functions are proteins, involved in all processes of Life, including the mechanisms by which cells respond to extracellular stimuli. One of the primary methods by which signals are passed between and within cells is via chemical modification of proteins, so called post-translational modifications (PTMs). These PTMs affect how a protein performs it function, for example acting as an on-off switch or by enabling (or blocking) interactions with other proteins. Perhaps the most important PTM is the reversible addition of chemical phosphate groups, termed phosphorylation, which is predicted to occur on around half of all human proteins. Changes or mistakes in protein phosphorylation are implicated in many diseases, and particularly in cancer, where altered phosphorylation of key 'signalling' proteins is a major contributing factor to cancer progression. The enzymes responsible for protein phosphorylation are called kinases, which themselves are often activated by the addition of phosphate, in a 'domino-effect' type cascade mechanism. Ultimately, these phosphorylation 'cascades' result in the activation of proteins called transcription factors, which switch on the expression of lots of new genes, thus making new proteins so the cell can respond to the signal received. As a result, the majority of current cancer drugs on the market or in development, target kinases directly or indirectly. For nearly half a century, we have known that three of the 20 amino acids that make up proteins are phosphorylated in vertebrates. Excitingly, we have now discovered that an additional 5 amino acids are extensively modified by phosphorylation in human cells, which we call pX proteins. These novel findings completely change our understanding of the landscape of this type of regulatory protein modification in human cells. Critically, the biological functions and regulatory mechanisms that underlie the addition and removal of this 'missing' phosphate have not yet been explained. In this project, we will develop a web-based database to make the evidence for these new types of phosphorylation straightforwardly available to other researchers. We will develop software tools to run within the database to allow us to hypothesise what functions these pX proteins perform in cells, and to allow us and other researchers to start exploring which kinases may be responsible for pX phosphorylation. These tools will also allow other researchers to apply these new findings to their own research questions, and help formulate hypotheses to be followed up in new studies.