ReviewBiochemistry

Illuminating the dark phosphoproteome

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Science Signaling  22 Jan 2019:
Vol. 12, Issue 565, eaau8645
DOI: 10.1126/scisignal.aau8645

Gloss

Protein phosphorylation is a posttranslational modification that regulates protein function. Many biological processes require phosphorylation, and its dysregulation is a hallmark of several complex diseases. Major developments in mass spectrometry now enable the measurement of thousands of changes in phosphorylation and mapping them to exact sites on specific proteins. More than 100,000 phosphorylation sites have been reported, but the kinases regulating these events are currently known only for a small fraction of these sites, and even fewer sites are linked to specific functions. A small subset of kinases dominates the annotated phosphosites, whereas many kinases have no known target proteins. Functional experiments linking human disease genes and mouse knockouts with kinases suggest that these lesser-studied kinases may also be important in health. This Review, with 4 figures, 4 videos, 3 data files, and 205 references, discusses how identifying regulatory kinases and functions of phosphorylated proteins will reveal mechanistic insights into biological function in healthy and disease contexts, point to new therapeutic targets, and enhance our understanding of drug action.

Abstract

Protein phosphorylation is a major regulator of protein function and biological outcomes. This was first recognized through functional biochemical experiments, and in the past decade, major technological advances in mass spectrometry have enabled the study of protein phosphorylation on a global scale. This rapidly growing field of phosphoproteomics has revealed that more than 100,000 distinct phosphorylation events occur in human cells, which likely affect the function of every protein. Phosphoproteomics has improved the understanding of the function of even the most well-characterized protein kinases by revealing new downstream substrates and biology. However, current biochemical and bioinformatic approaches have only identified kinases for less than 5% of the phosphoproteome, and functional assignments of phosphosites are almost negligible. Notably, our understanding of the relationship between kinases and their substrates follows a power law distribution, with almost 90% of phosphorylation sites currently assigned to the top 20% of kinases. In addition, more than 150 kinases do not have a single known substrate. Despite a small group of kinases dominating biomedical research, the number of substrates assigned to a kinase does not correlate with disease relevance as determined by pathogenic human mutation prevalence and mouse model phenotypes. Improving our understanding of the substrates targeted by all kinases and functionally annotating the phosphoproteome will be broadly beneficial. Advances in phosphoproteomics technologies, combined with functional screening approaches, should make it feasible to illuminate the connectivity and functionality of the entire phosphoproteome, providing enormous opportunities for discovering new biology, therapeutic targets, and possibly diagnostics.

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