Referee 1's review:

This paper presents an integrated steady-state model of 3 yeast signaling networks. Each of the 3 networks, and the mathematical methodology employed were previously developed and published by the corresponding author and colleagues. The main contribution of the current model is the integration, showing coordination of signaling activity across the three pathways.

I cannot comment on the biology of the systems modeled. But I have read Dr. Venkatesh's earlier papers on the individual network models; discussed them with others, and found them to be solid. The computational modeling methodology used is sound and well described.

I have a few comments that I hope will improve the quality of the manuscript. Firstly, I would urge the authors (and PLoS Editors?) to correct the many grammatical errors in the text (which start with the first sentence of the abstract). Sentences in the current MS frequently mix present and past tense, singular and plural, etc. I found myself reading many sentences 2 or 3 times before I could understand them. I realize it is not fair to ask authors for whom English is not a mother tongue to write better English. But judging by Dr. Venkatesh's previous articles, correct grammar is easily within reach of the authors.

On the technical side, a fairly large number of the parameters for the proposed model are found by fitting the model to observations. Several of the parameters estimated in this way seem unusually large. In particular, several estimated Hill Coefficients are greater than 3, the worst being a Hill coefficient of 8 for the dependence of FLO11 on ammonium sulfate concentration. These values seem biologically implausible or at least unusually high. The authors should discuss the plausibility of each case, either providing supporting evidence, or at least commenting on possible causes (e.g. they might represent compounded coefficients arising from a series of reactions that have been simplified into one step here).

Similarly, on p11 of the Supplementary Materials, K, K4, and K9 are three orders of magnitude larger than other rates, but no justification is provided.

Another point, the authors repeatedly state that the FLO11 switch is irreversible, for example (p19):

"Moreover, the simulated dose response for the expression of FLO11 showed a bistable behavior, which was irreversible in response to varying concentration of ammonium sulphate."

Do the authors really mean that once the switch is flipped , it cannot be reset? If so they should provide greater justification for the assertion. The simulation results presented suggest the system _is_ reversible with 2 thresholds (like all bistable systems).

Finally, I found the presentation of the experiment data in Figures 3 and 8 confusing. The caption of figure 3 does not say that experimental data is included in the figure, but the points shown are the same as in figure 8 , which states:

"The experimental values for expression of FLO11 with cells precultured in nitrogen rich media (triangle) and nitrogen starved media (x) are indicated."

My issue is that the (x) data do not fall on any shown simulation trajectory. Can the model reproduce this data? If not, what is point of showing the data?

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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.