Abstract
Protein phosphorylation underlies cellular response pathways across eukaryotes and is governed by the opposing actions of phosphorylating kinases and de-phosphorylating phosphatases. While kinases and phosphatases have been extensively studied, their organization and the mechanisms by which they balance each other are not well understood. To address these questions we performed quantitative analyses of large-scale 'omics' datasets from yeast, fly, plant, mouse and human. We uncovered an asymmetric balance of a previously-hidden scale: Each organism contained many different kinase genes, and these were balanced by a small set of highly abundant phosphatase proteins. Kinases were much more responsive to perturbations at the gene and protein levels. In addition, kinases had diverse scales of phenotypic impact when manipulated. Phosphatases, in contrast, were stable, highly robust and flatly organized, with rather uniform impact downstream. We validated aspects of this organization experimentally in nematode, and supported additional aspects by theoretic analysis of the dynamics of protein phosphorylation. Our analyses explain the empirical bias in the protein phosphorylation field toward characterization and therapeutic targeting of kinases at the expense of phosphatases. We show quantitatively and broadly that this is not only a historical bias, but stems from wide-ranging differences in their organization and impact. The asymmetric balance between these opposing regulators of protein phosphorylation is also common to opposing regulators of two other post-translational modification systems, suggesting its fundamental value.
Highlights
The study of protein phosphorylation concentrated on the role of kinases, which introduce the phosphate, at the expense of phosphatases, which remove it
Kinases and Phosphatases Are Asymmetrically Balanced across Eukaryotes considered attractive drug targets, while phosphatases remained far less characterized. It has been unclear whether this discrepancy is due to historical biases or reflects real systemic differences between these enzymes
By analyzing large-scale ‘omics’ datasets across genes, transcripts, proteins, interactions, and organisms, we uncovered an asymmetric architecture of kinases versus phosphatases that balances between them, determines their distinct impact patterns, and affects their therapeutic potential. This architecture is conserved from yeast to human and is partially shared by two other protein modification systems, suggesting it is a general feature of these systems
Summary
Protein phosphorylation is a common post-translational modification, in which a phosphate group is covalently attached to amino acid residues within a protein by the function of a kinase. The phosphorylated protein may acquire a different reactivity, interaction specificity or cellular localization, which allow it to carry functions that the unmodified protein could not [1]. Upon removal of the phosphate group by the function of a phosphatase, the de-phosphorylated protein regains its previous functionality [2,3,4]. Reversible protein phosphorylation underlies signal transduction and controls main cellular processes across eukaryotes, such as cell-cycle, metabolism, transcription and translation [5]. Protein phosphorylation is under strict regulation, and is governed by the balanced actions of kinases and phosphatases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
