An Atlas of Human Kinase Regulation

David Ochoa, Mindaugas Jonikas, Robert T Lawrence, Bachir El Debs, Joel Selkrig, Athanasios Typas, Judit Villén, Silvia DM Santos, Pedro Beltrao

Now published in Molecular Systems Biology 10.15252/msb.20167295

AbstractThe coordinated regulation of protein kinases is a rapid mechanism that integrates diverse cues and swiftly determines appropriate cellular responses. However, our understanding of cellular decision-making has been limited by the small number of simultaneously monitored phospho-regulatory events. Here, we have estimated changes in activity in 215 human kinases in 399 conditions derived from a large compilation of phosphopeptide quantifications. This atlas identifies commonly regulated kinases as those that are central in the signaling network and defines the logic relationships between kinase pairs. Co-regulation along the conditions predicts kinase-complex and kinase-substrate associations. Additionally, the kinase regulation profile acts as a molecular fingerprint to identify related and opposing signaling states. Using this atlas, we identified essential mediators of stem cell differentiation, modulators of Salmonella infection and new targets of AKT1. This provides a global view of human phosphorylation-based signaling and the necessary context to better understand kinase driven decision-making.

Introduction

Cells need to constantly adapt to internal and external conditions in order to maintain homoeostasis. During cellular decision-making, signal-transduction networks dynamically change in response to cues, triggering cellular state-defining responses. Multiple mechanisms exist to transfer this information from sensors to the corresponding molecular responses, one of the fastest being the reversible post-translational modification of proteins (PTMs). Through these targeted modifications, such as phosphorylation, the cell can quickly alter enzymatic activities, protein interactions or sub-cellular localization in order to produce a coordinated response to a given stimulus (Pawson 2004). Protein phospho-regulation constitutes a highly conserved regulatory mechanism relevant for a broad set of biological functions and diseases (Beltrao 2012).

Over the past decades, our view of cellular signaling has advanced from an idea of isolated and linear cascades to highly complex and cooperative regulatory networks (Jordan 2000, Gibson 2009). Different perturbations in cellular conditions often activate different sets of interconnected kinases, ultimately triggering appropriate cellular responses. The complete understanding of such cell-fate decisions would require the systematic measurement of changes in kinase activities under multiple perturbations, but the small number of quantified regulatory events (i.e. tens) that were possible to date has limited our knowledge of cellular decision making and its molecular consequences (Kim 2011, Bendall 2011, Niepel 2013,