title: Crosstalk between cAMP-PKA and MAP kinase pathways is a key regulatory design necessary to regulate FLO11 expression.
abstract: Signal transduction pathways crosstalk with one another and play a central role in regulation of cellular events. Crosstalk brings complexity to the system, and hence, a systematic analysis of these crosstalks helps in relating the signaling network structure to its function. Here, we present a modular steady state approach to quantify the network comprising of cAMP-PKA and MAP kinase pathways involved in the regulation of FLO11, a gene which is required for pseudohyphae growth in Saccharomyces cerevisiae under nitrogen starvation. These two pathways crosstalk by converging on the same target, i.e., FLO11 and through Ras2p, an upstream activator of both cAMP and MAPK pathway. Analysis of crosstalk at the gene level revealed that cAMP-PKA and MAPK pathways are indispensable to FLO11 expression. The dose response was highly sensitive and primarily controlled by cAMP-PKA pathway. We demonstrate that the highly sensitive response in the cAMP-PKA pathway was due to crosstalk and inhibitor ultrsensitivity, key regulatory designs present at the downstream of cAMP-PKA pathway. The analysis of the role of Ras2p in the crosstalk between the cAMP-PKA and MAPK pathways indicated that crosstalk essentially helped in amplification of the Gpa2p signal, another upstream activator of the cAMP-PKA pathway. However, the effect of crosstalk due to Ras2p on FLO11 expression was minimal under normal activation levels of Ras2p. Whereas, the crosstalk itself can bring about FLO11 expression under the hyperactivated Ras2p conditions thereby eliminating the requirement for the other activator Gpa2p. We also observed the presence of system level properties such as amplification, inhibitor ultrasensitvity and bistability, which can be attributed to the regulatory design present in the FLO11 expression system. These system level properties might help the organism to respond to varying nutritional status.
authors.affiliation: Biosystems Engineering Laboratory, Department of Chemical Engineering and School of Biosciences and Bioengineering, Indian Institute of Technology, Bombay, Powai, Mumbai-400 076, India.
authors.forename: Neelanjan
authors.initials: N
authors.lastname: Sengupta
authors.forename: P K
authors.initials: PK
authors.lastname: Vinod
authors.forename: K V
authors.initials: KV
authors.lastname: Venkatesh
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology; D044385:GTP-Binding Protein alpha Subunits / Q000502:physiology; D015966:Gene Expression Regulation, Fungal; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000254:growth & development / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D018631:ras Proteins / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C110690:FLO11 protein, S cerevisiae; C100940:FLO8 protein, S cerevisaie; D044385:GTP-Binding Protein alpha Subunits; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C489241:STE12 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C069926:TEC1 protein, S cerevisiae; D015534:Trans-Activators; D014157:Transcription Factors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C083907:Gpa2 protein, S cerevisiae; C489015:RAS2 protein, S cerevisiae; D018631:ras Proteins; D000262:Adenylyl Cyclases