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Abstract Bacteria possess diverse classes of signaling systems that they use to sense and respond to their environments and execute properly timed developmental transitions. One widespread and evolutionarily ancient class of signaling systems are the Hanks‐type Ser/Thr kinases, also sometimes termed “eukaryotic‐like” due to their homology with eukaryotic kinases. In diverse bacterial species, these signaling systems function as critical regulators of general cellular processes such as metabolism, growth and division, developmental transitions such as sporulation, biofilm formation, and virulence, as well as antibiotic tolerance. This multifaceted regulation is due to the ability of a single Hanks‐type Ser/Thr kinase to post‐translationally modify the activity of multiple proteins, resulting in the coordinated regulation of diverse cellular pathways. However, in part due to their deep integration with cellular physiology, to date, we have a relatively limited understanding of the timing, regulatory hierarchy, the complete list of targets of a given kinase, as well as the potential regulatory overlap between the often multiple kinases present in a single organism. In this review, we discuss experimental methods and curated datasets aimed at elucidating the targets of these signaling pathways and approaches for using these datasets to develop computational models for quantitative predictions of target motifs. We emphasize novel approaches and opportunities for collecting data suitable for the creation of new predictive computational models applicable to diverse species. 

The Heat Shock Response (HSR) is a highly conserved genetic system charged with protecting the proteome in a wide range of organisms and species. Experiments since the early 1980s have elucidated key elements in these pathways and revealed a canonical mode of regulation, which relies on a titration feedback. This system has been subject to substantial modeling work, addressing questions about resilience, design and control. The compact core regulatory circuit, as well as its apparent conservation, make this system an ideal ‘hydrogen atom’ model for the regulation of stress response. Here we take a broad view of the models of the HSR, focusing on the different questions asked and the approaches taken. After 20 years of modeling work, we ask what lessons had been learned that would have been hard to discover without mathematical models. We find that while existing models lay strong foundations, many important questions that can benefit from quantitative modeling are still awaiting investigation.