Physiology and genetic regulation of cellular signal transmission

Roger Brent (MSI)

Abstract

The Alpha project seeks comprehensive understanding of quantitative behavior of the yeast mating pheromone response system by 2012. In the past year we have made a great deal of progress in understanding the quantitative physiology of this cellular information transmitting system, defined key quantitative aspects of system function, and defined genetic mechanisms that govern these quantitative behaviors. It seems likely that many of these findings will be fundamental in the sense that they will be widely found in cellular systems of this type. The goal is to enable a comprehensive formal understanding of information transmission and its genetic control for all the information transmission systems encoded by the genomes of higher eukaryotes.

The workhorse experiment is to stimulate the system with defined input by exposing yeast cells to defined concentrations of pheromone. Cells are all closely related to a reference strain but differ in reporters they carry and in other defined genetic lesions. Progress relies on genetics, fluidic technology (U Washington and MIT), optical means to interrogate cells, protein mass spectrometry (Pacific Northwest National Labs), and computational, mathematical (Caltech, MIT), and conceptual work to explain the findings and abstract key elements from them.

We divide signal transmission into initial signal propagation and establishment. Propagation is relatively slow; signal takes minutes to get to the nucleus. At each point along the chain of transmission, signal rises, overshoots, peaks, and is reduced toward equilibrium by negative feedback. The effect of this feedback is to maximize information transmitted through the system about percent receptor occupancy. This property enables an exquisitely graded response to small differences in initial stimulus. Consistent with this idea, the system shows neither desensitization nor potentiation for many hours after initial stimulation; superstimulation above baseline causes results a secondary signal transmitted at the same speed with no decrease in incremental signal amplitude.

The system regulates its quantitative behavior to preserve the important information carried by the signal, which is about pheromone dose, in most cases corresponding to percent receptor occupancy. Preservation of dose information occurs over time, in the face of significant changes in the numbers of its protein components. Put differently, one major function of the system is to preserve signal information content, to prevent information about dose carried by the signal from being degraded. Preservation of dose information seems to depend on numerous, inducible, regulatory phosphorylation feedback events revealed by "deep dive" mass spectrometric proteomics experiments. Targeted genetic experiments have begun to reveal the functions of these individual feedbacks, which, in totality, keep system behavior on track to preserve signal information content as above.

Work at the CQGF is supported by a Center of Excellence in Genomic Sciences grant from the US National Human Genome Research Institute.

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