We study how eukaryotic cells sense nutrients and regulate TORC1, a highly-conserved kinase that controls cell growth and metabolism. Our work in Saccharomyces cerevisiae has revealed that upstream regulators like Gtr1/2 and Pib2 cooperate to push TORC1 into three distinct activity states. These states determine whether cells grow rapidly, adapt to poor nutrient conditions, or enter quiescence (Cecil et al., eLife 2025).
Evolution and Rewiring of the TORC1 Signaling Network
In some yeast lineages, the TORC1 regulatory network has undergone extensive rewiring. We recently discovered Ait1, a GPCR-like protein that localizes to the vacuolar membrane and directly binds/regulates TORC1 and Gtr1/2 during amino acid starvation. Ait1 is found only in the Saccharomycetaceae and codocea—closely related clades of budding yeast that have lost the ancient TORC1 regulators Rheb and TSC1/2 (Wallace et al., eLife 2022).
TORC1 Body Formation and Protein Aggregation as a Regulatory Strategy
We discovered that TORC1 relocalizes to bodies on the vacuolar membrane during starvation. This relocalization regulates TORC1 activity and helps set a high threshold for reactivation. Through genetic and imaging approaches, we’ve identified dozens of regulators of TORC1-body formation and shown how proteins like Pib2 and Snf1/AMPK modulate this process to encode cellular memory and hysteresis (Sullivan et al., MBoC 2019; Hughes Hallett et al., eLife 2015).
Signal Integration and Dynamic Phosphorylation Networks
We use phosphoproteomics to determine how signaling networks encode and transmit information. Our recent work revealed that PKA has different affinity for different substrates, enabling PKA to drive condition-specific signaling programs. This graded output helps cells transition smoothly between different growth states (Plank et al., MBoC 2024).
TORC1–PKA Crosstalk and Transcriptional Control
TORC1 and PKA converge on numerous transcription factors that regulate ribosome biogenesis and metabolism. We study how this signal integration enables cells to tune gene expression based on both internal metabolite levels (via TORC1) and external carbon sources (via PKA). Using chemical-genetic perturbations, time-course transcriptomics, and single-cell imaging, we are studying how these circuits coordinate cellular decisions (Kunkel et al., Nat Commun 2019).
Information Processing in Signaling Networks
Our long-term goal is to define how signaling networks act as information-processing circuits. Using genetic and phosphoproteomic tools, we identify regulatory motifs—such as feedback loops, bistable switches, and logic gates—that allow cells to make context-specific decisions about growth, stress resistance, and quiescence (Hughes Hallett et al., Genetics 2014; Capaldi et al., Nat Genet 2008).
Relevance to Broader Eukaryotic Systems
Although we study signaling and gene regulation in the budding yeast S. cerevisiae, many of the regulatory principles we uncover—such as feedback control, signal thresholds, condition dependent outputs, and rewiring—are relevant across eukaryotes. Dysregulation of TORC1 and PKA signaling underlies aging, cancer, and metabolic disorders in humans, and our work provides a foundation for understanding these processes from first principles.
