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Model of the Ras/cAMP/PKA pathway in S. cerevisiae

In the yeast Saccharomyces cerevisiae, the Ras/cAMP/PKA pathway plays a major role in the regulation of metabolism, stress resistance and cell cycle progression.

This signaling cascade is tightly regulated. The cyclic adenosine monophosphate (cAMP) is synthesized by the adenylate cyclase, and induces the activation of the cAMP-dependent protein kinase A (PKA). The adenylate cyclase activity is controlled by Ras proteins (Ras1 and Ras2), and Gpa2 protein. Ras proteins are monomeric GTPases that cycle between an inactive state, bound to GDP, and an active state, associated to GTP. Ras proteins are positively controlled by the activity of Cdc25, a Guanine Nucleotide Exchange Factor (GEF), that stimulates the GDP-GTP exchange, and negatively regulated by Ira1 and Ira2, two GTPase Activating Proteins (GAP), that stimulate the GTPase activity of Ras.
The inactivation of cAMP is governed by phosphodiesterases, Pde1 and Pde2, that constitute a major feedback mechanism in the pathway.

Download the model

The SBML version of the model is available here

A diagram of all reactions between molecular species is also available here

Reference papers

D. Pescini, P. Cazzaniga, D. Besozzi, G. Mauri, S. Colombo, E. Martegani.
Simulation of the Ras/cAMP/PKA pathway in budding yeast highlights the establishment of stable oscillatory states.
Biotechnology Advances, to appear.

D. Besozzi,, P. Cazzaniga, D. Pescini, G. Mauri, S. Colombo, E. Martegani.
Investigating oscillatory regimens in the Ras/cAMP/PKA pathway S. cerevisiae: the role of feedback control mechanisms.
Proceedings of 8th International Workshop on Computational Systems Biology (WCSB 2011), June 6-8, 2011 Zurich, Switzerland, to appear.

P. Cazzaniga, D. Pescini, D. Besozzi, G. Mauri, S. Colombo, E. Martegani.
Modeling and stochastic simulation of the Ras/cAMP/PKA pathway in the yeast Saccharomyces cerevisiae evidences a key regulatory function for intracellular guanine nucleotides pools.
Journal of Biotechnology, Vol. 133, Issue 3, 377-385, 2008.

Model of Bacterial Chemotaxis

Chemotaxis is an efficient signal transduction pathway which allows bacterial cells to move directionally, in response to specific attractants or repellents occurring in their surroundings. The pathway consists of several  transmembrane and cytoplasmic proteins acting as signal sensors and response regulators, which rule the reversal of the flagellar motor
(governed by the phosphorylation and dephosphorylation of a key protein, CheY).
In homogeneous environments, this process induces a switch between running and tumbling movements, with a frequency that allows a temporal sampling (through random walks) of the surrounding space. On the contrary, in the presence of a gradient of attractants or repellents, bacteria are able to respond quickly by reducing the frequency of flagellar reversal between clockwise and counterclockwise rotations, which cause a longer running motion in a biased direction. The frequency of switching is then reset to the random walk level if the concentration of the external ligands remains constant in time. At the molecular scale, this adaptation property is implemented by the coordinated action of methyltransferase and methylesterase proteins acting on the transmembrane receptors.

The SBML version of the model is available here

Reference papers

D. Besozzi, P. Cazzaniga, M. Dugo, D. Pescini, G. Mauri.
A study on the combined interplay between stochastic fluctuations and the number of flagella in bacterial chemotaxis.
Proceedings of CompMod2009 – 2nd International Workshop on Computational Models for Cell Processes (R.J. Back, I. Petre, E. de Vink, eds.), EPTCS 6, 47–62, 2009.


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