Fus3-triggered Tec1 degradation modulates mating transcriptional output during the pheromone response

Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.
Molecular Systems Biology (Impact Factor: 14.1). 02/2008; 4:212. DOI: 10.1038/msb.2008.47
Source: PubMed

ABSTRACT The yeast transcription factor Ste12 controls both mating and filamentation pathways. Upon pheromone induction, the mitogen-activated protein kinases, Fus3 and Kss1, activate Ste12 by relieving the repression of two functionally redundant Ste12 inhibitors, Dig1 and Dig2. Mating genes are controlled by the Ste12/Dig1/Dig2 complex through Ste12-binding sites, whereas filamentation genes are regulated by the Tec1/Ste12/Dig1 complex through Tec1-binding sites. The two Ste12 complexes are mutually exclusive. During pheromone response, Tec1 is degraded upon phosphorylation by Fus3, preventing cross-activation of the filamentation pathway. Here, we show that a stable Tec1 also impairs the induction of mating genes. A mathematical model is developed to capture the dynamic formation of the two Ste12 complexes and their interactions with pathway-specific promoters. By model simulations and experimentation, we show that excess Tec1 can impair the mating transcriptional output because of its ability to sequester Ste12, and because of a novel function of Dig2 for the transcription of mating genes. We suggest that Fus3-triggered Tec1 degradation is an important part of the transcriptional induction of mating genes during the pheromone response.

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Available from: Su Zhao, Aug 08, 2015
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    • "Therefore, a potential mechanism for Dig2's positive role in transcriptional induction is that Dig2 prevents the formation of Ste12–Tec1 heterodimers, providing a larger pool of Ste12 multimers for activation of the mating transcriptional program. However, Chou et al (2008) found that Dig2's positive effect on transcription is independent of Tec1, eliminating this possibility. A second way that Dig2 could have a positive role in transcription would be for Dig2 to protect Ste12 from degradation. "
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    ABSTRACT: All cells must detect and respond to changes in their environment, often through changes in gene expression. The yeast pheromone pathway has been extensively characterized, and is an ideal system for studying transcriptional regulation. Here we combine computational and experimental approaches to study transcriptional regulation mediated by Ste12, the key transcription factor in the pheromone response. Our mathematical model is able to explain multiple counterintuitive experimental results and led to several novel findings. First, we found that the transcriptional repressors Dig1 and Dig2 positively affect transcription by stabilizing Ste12. This stabilization through protein-protein interactions creates a large pool of Ste12 that is rapidly activated following pheromone stimulation. Second, we found that protein degradation follows saturating kinetics, explaining the long half-life of Ste12 in mutants expressing elevated amounts of Ste12. Finally, our model reveals a novel mechanism for robust perfect adaptation through protein-protein interactions that enhance complex stability. This mechanism allows the transcriptional response to act on a shorter time scale than upstream pathway activity.
    Molecular Systems Biology 06/2012; 8:586. DOI:10.1038/msb.2012.18 · 14.10 Impact Factor
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    • "In S. cerevisiae, the Fus3-and the Kss1-related MAPK pathways converge on the Ste12 transcription factor to regulate mating or filamentation, respectively, in response to different stimuli. Signaling specificity is achieved by selective ubiquitination and sumoylation of Ste12 and its cofactor Tec1, leading to either degradation or protection of the respective transcription factors (Bruckner et al., 2004; Chou et al., 2008). Cross-activation of AtfA and OsrA in A. fumigatus could be prevented by a similar interplay between ubiquitination and sumoylation . "
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    Molecular biology of the cell 06/2011; 22(11):1896-906. DOI:10.1091/mbc.E10-11-0914 · 5.98 Impact Factor
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    • "Both mating and filamentation pathways have genetic positive feedback loops, as both Ste12 and Tec1 up-regulate themselves [20]. A variety of mechanisms have been proposed and studied to explain the signaling specificity in yeast cells, including the sequestration of shared components by scaffold proteins [21] [22], the experimental identification of Fus3-dependent inhibition on Tec1 [18] [19] [23], and the resource draining of Ste12 by Tec1 binding and Ste12-Tec1 degradation [11]. Since there is no absolute physical separation of the MAPK-dependent pathways, cross-pathway inhibition is the likely solution to promote signaling specificity. "
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    ABSTRACT: Cells sense and respond to diverse environmental stimuli using a set of intracellular signaling components. Often, the signal transduction pathways contain shared components which lead to cross activation at different levels of the pathway. To discover the design principles that ensure signaling specificity is a challenging task, especially for pathways that contain numerous components. Here, we present an analysis of cross-activating pathways and show that a general inhibitory scheme, asymmetric hierarchical inhibition, is sufficient to ensure signaling specificity. Based on this inhibitory scheme, we are able to enumerate all possible network topologies containing two inhibitory links that guarantee specificity. Furthermore, we apply our methodology to the mating and filamentous growth pathways of the yeast model system Saccharomyces cerevisiae. We enumerate the possible ways to wire this model system and determine which topology is consistent with experimental data.
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