Dose response alignment in a G protein coupled receptor pathway

ALAN BUSH; ARIEL CHERNOMORETZ; ALEJANDRO COLMAN-LERNER

Montevideo, Uruguay

Congreso; International Society of Computational Biology-Latin America; 2010

International society for computational biology

Cells sense their environment and make decisions based on external clues, transmitting information inside the cell by signal transduction pathways. The pathway used by haploid cells of Saccharomyces cerevisiae to respond to the opposite mating type pheromone [1] , is comprised of a G Protein Coupled Receptor (GPCR) which, when bound to its agonist, stimulates the dissociation of the heterotrimeric G protein. Free Gβγ heterodimer recruits to the membrane the scaffold protein Ste5. At the membrane, Ste5 assembles the components of a MAP kinase cascade leading to the activation by phosphorylation of Fus3MAPK. Activated Fus3 translocates to the nucleus, where it causes cell cycle arrest and induces the expression of mating genes. The Dose Response (DoR) curves measured at various levels down the pheromone pathway show a good alignment, a phenomenon called DoRA (for “DoR Alignment”)[2]. DoRA helps maintain fidelity in the information transmission and, though apparently intuitive, it is not easily explained from the underlying highly non-linear biochemistry that takes place during signal transmission. Furthermore, we and others have shown that this alignment depends on the activity of key components of the pathway, as the MAPK Fus3 and the RGS (Regulator of G Protein Signaling) Sst2. In this work we measured the recruitment dynamics of the scaffold protein Ste5 to the membrane in a quantitative manner. The DoR curve at this measurement point shows some degree of alignment with the receptor occupancy and the transcriptional induction. Interestingly enough the DoR curve for Ste5 translocation seems to stabilize before the receptor reaches steady state, “anticipating” the levels of occupancy that the receptor will reach in the future. A simple mathematical model and some preliminary data suggest that a fast activation of Sst2 can explain the anticipation phenomenon.