Delineating functional principles of the bow tie structure of a kinase-phosphatase network in the budding yeast

Diala Abd-Rabbo,Stephen W Michnick

doi:10.1186/s12918-017-0418-0

Abstract

BackgroundKinases and phosphatases (KP) form complex self-regulating networks essential for cellular signal processing. In spite of having a wealth of data about interactions among KPs and their substrates, we have very limited models of the structures of the directed networks they form and consequently our ability to formulate hypotheses about how their structure determines the flow of information in these networks is restricted.ResultsWe assembled and studied the largest bona fide kinase-phosphatase network (KP-Net) known to date for the yeast Saccharomyces cerevisiae. Application of the vertex sort (VS) algorithm on the KP-Net allowed us to elucidate its hierarchical structure in which nodes are sorted into top, core and bottom layers, forming a bow tie structure with a strongly connected core layer. Surprisingly, phosphatases tend to sort into the top layer, implying they are less regulated by phosphorylation than kinases. Superposition of the widest range of KP biological properties over the KP-Net hierarchy shows that core layer KPs: (i), receive the largest number of inputs; (ii), form bottlenecks implicated in multiple pathways and in decision-making; (iii), and are among the most regulated KPs both temporally and spatially. Moreover, top layer KPs are more abundant and less noisy than those in the bottom layer. Finally, we showed that the VS algorithm depends on node degrees without biasing the biological results of the sorted network. The VS algorithm is available as an R package (https://cran.r-project.org/web/packages/VertexSort/index.html).ConclusionsThe KP-Net model we propose possesses a bow tie hierarchical structure in which the top layer appears to ensure highest fidelity and the core layer appears to mediate signal integration and cell state-dependent signal interpretation. Our model of the yeast KP-Net provides both functional insight into its organization as we understand today and a framework for future investigation of information processing in yeast and eukaryotes in general.

Highlights

Kinases and phosphatases (KP) form complex self-regulating networks essential for cellular signal processing
To ensure that the interactions assembled in the kinase-phosphatase network (KP-Net) represent phosphorylation and dephosphorylation interactions (PDI) rather than Kinase-protein or phosphataseprotein interactions, we selected interactions having a confidence score ≥ 4.52 and those validated by at least one biochemical experiment showing the occurrence of a PDI
Difference between findings of Cheng et al and those of this study might be due to the following reasons: (i), the lack of phosphatases in the network analysed by Cheng et al.; (ii), the high number of false positives that normally exist in any data generated in vitro, which could affect sorting of nodes in the different layers and directly affect layer properties; (iii), the application of a decomposition method differing from the vertex sort (VS) algorithm, (iv), or a combination of all these reasons

Summary

Introduction

Kinases and phosphatases (KP) form complex self-regulating networks essential for cellular signal processing. Protein KPs play an essential regulatory role in signalling pathways through phosphorylation and dephosphorylation interactions (PDI) that cause profound effects on substrates, Numerous efforts have been made to reconstruct the budding yeast KP-Net from various types of interactions [2,3,4,5,6,7]. Despite these efforts, KP-Nets assembled so far are not fully mature to represent genuine networks in which a KP acts directly on its substrate for the following reasons. Constructing a bona fide KP-Net remains an essential goal for analysis of signalling networks

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Conclusion