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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-017-0418-0) contains supplementary material, which is available to authorized users.

Protein phosphatases of Saccharomyces cerevisiae

“…Another difference between kinases and phosphatases is the abundance; phosphatases in general are much more abundant in the cell than kinases and have longer half-lives (Smoly et al, 2017). Also, phosphatases are regulated more by the binding of different subunits (Abd-Rabbo and Michnick, 2017) , while kinases are regulated more often by phosphorylation (Rubenstein and Schmidt, 2007).…”

Bow-tie motifs enable protein multifunctionality by connecting cellular processes in the interactome

“…The bow-tie is a well-known network topological motif [15][16][17]. In cell biology, however, it has been identified only in signaling-and metabolic networks [16,20,32,33]. Here, we greatly expand upon the bow-tie motif's application in protein interactomes, showing that it is far more abundant than previously demonstrated, and that it populates functionally diverse areas of the protein interactome, many of which are not signaling networks.…”

“…Here, we greatly expand upon the bow-tie motif's application in protein interactomes, showing that it is far more abundant than previously demonstrated, and that it populates functionally diverse areas of the protein interactome, many of which are not signaling networks. By presenting the bow-tie motif in the context of the intermediate topological level, we also show that the bow-tie motif not only connects upper and lower parts of signaling cascades, which is well-known [20,32], but that its main application may in fact be connecting distinct cellular processes. We find that the design of the bow-tie motif seems to allow "knot" proteins to be recruited by alternating cellular processes via their interaction fans when needed.…”

Complete Topological Mapping of a Cellular Protein Interactome Reveals Bow-Tie Motifs as Ubiquitous Connectors of Protein Complexes

“…Protein complexes and hub proteins have been extensively studied at an interactome-wide level, using community detection algorithms to find protein complexes and using the high degree as a selection criterion to find hub proteins. In contrast, bow-tie motifs have been detected only a few times in PPI networks (Oda and Kitano, 2006;Polouliakh et al, 2009;Abd-Rabbo and Michnick, 2017), and their potential role as recurring connectors of protein complexes has not been investigated. Therefore, to obtain an overview of the bow-tie motifs in the cDC1 interactome, we cataloged the ''knot'' proteins and their interaction fans using a two-step process.…”