Kofahl and Klipp (2004), Yeast Pheromone Pathway
January 2008, model of the month by Melanie I. Stefan
Original model: BIOMD0000000032
Haploid Saccharomyces cerevisiae exists in one of two types, a or α, which can mate with each other. Cells of type α secrete a specific pheromone, which is recognised by surface receptors on a cells, and vice versa. Binding of pheromone to the receptor triggers a reaction pathway that ultimately results in cell cycle arrest in phase G1 and fusion with a cell of the opposite mating type to form a diploid cell .
While a and α type cells display different pheromone receptors, the rest of the pathway inducing preparation for mating is the same in both types (reviewed in [2,3]). The pathway comprises several modules: Receptor activation triggers a G-protein cycle, whereby Gβγ is produced. Independently of receptor activation, a scaffold complex forms, to which Gβγ binds. This interaction is necessary for the ensuing MAPK cascade, which leads to repeated activation of various molecules of Fus3. Active Fus3, in turn, triggers the modules necessary for polarised growth, cell cycle arrest and alterations in gene expression and thus prepares the cell for mating. The complete pathway is shown in Figure 1.
Kofahl and Klipp  (BIOMD0000000032) used a system of ordinary differential equations to model the pheromone response pathway of a cells. All the modules described above were broken down into a set of reactions. For instance, the receptor activation module includes not only reversible binding of α factor to the Ste2 receptor, but also possible degradation of the pheromone by Bar1 and receptor downregulation and degradation. For a full scheme of reactions, see figure 1. The total model comprises 47 reactions (see Figure 1), described by 35 differential equations. Since the yeast pheromone pathway is a very well-studied system, the authors were able to take many of the parameter values from experimental literature. Models describing sixteen well-characterised yeast mutants were obtained from the original model by altering specific reaction rates or concentrations. Numerical simulations were performed on all of these models.
The model made it possible to study the time course of various phosphorylation and complex formation events in wildtype as well as in mutants (e.g. Figure 2). It has since served as a basis for the development of more complex models, including models that account for multiple subcellular compartments  or models exploring the links between different pathways .
Figure 2: Expression of Fus3PP in wildtype and various pheromone hypersensitivity mutants. Figure taken from .
Figure 1: Yeast pheromone pathway. Figure taken from 
- H. Lodish, A. Berk, L. S. Zipursky, P. Matsudaira, D. Baltimore, and J. Darnell. Molecular Cell Biology. W. H. Freeman, 2000.
- J. Kurjan. Pheromone response in yeast. Annu Rev Biochem, 61:1097-1129, 1992. [SRS@EBI]
- E. A. Elion. Pheromone response, mating and cell biology. Curr Opin Microbiol, 3:573-581, 2000. [SRS@EBI]
- B. Kofahl and E. Klipp.Modelling the dynamics of the yeast pheromone pathway. Yeast, 21:831-850, 2004. [SRS@EBI]
- D. Shao, W. Zheng, W. Qiu, Q. Ouyang, and C. Tang. Dynamic studies of scaffold-dependent mating pathway in yeast. Biophys J, 91:3986-4001, 2006. [SRS@EBI]
- J. Schaber, B. Kofahl, A. Kowald, and E. Klipp. A modelling approach to quantify dynamic crosstalk between the pheromone and the starvation pathway in baker's yeast. FEBS J, 273:3520-3533, 2006. [SRS@EBI]