Dynamic Signaling in the Hog1 MAPK Pathway Relies on High Basal Signal Transduction

Macía, Javier; Regot, Sergi; Peeters, Tom; Conde-Pueyo, Núria; Solé, Ricard V.; Posas, Francesc

doi:10.1126/scisignal.2000056

Cited by 126 publications

(172 citation statements)

References 38 publications

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“…The H4b linker domain plays an essential role for the "on-off" transition of poly-HAMP conformation, whereas the H3b and H2b linkers appeared to have a facultative role in signal propagation. The HOG pathway maintains a basal level of signaling even under ambient conditions and which allows more rapid response and fine tuning of signaling thresholds upon stress treatments (42,43). The poly-HAMP structure can provide such a dynamic switch through the concerted motion that could be disrupted in the changing cytoplasmic environment under high osmolarity stress.…”

Section: Discussionmentioning

confidence: 99%

Differential Role of HAMP-like Linkers in Regulating the Functionality of the Group III Histidine Kinase DhNik1p

Kaur

Singh

Rathore

et al. 2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Differential Role of HAMP-like Linkers in Regulating the Functionality of the Group III Histidine Kinase DhNik1p

Kaur

Singh

Rathore

et al. 2014

Journal of Biological Chemistry

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“…Basal ERK activity enhances cell substrate interactions (14) and is essential for survival of quiescent, unstimulated cells (15). In yeast, basal activity in one branch of the Hog1 MAPK pathway, combined with negative feedback from Hog1, results in faster response to osmotic stress and higher sensitivity to external signals (16).…”

mentioning

confidence: 99%

Information transfer by leaky, heterogeneous, protein kinase signaling systems

Voliotis¹,

Perrett

McWilliams³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

122

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Cells must sense extracellular signals and transfer the information contained about their environment reliably to make appropriate decisions. To perform these tasks, cells use signal transduction networks that are subject to various sources of noise. Here, we study the effects on information transfer of two particular types of noise: basal (leaky) network activity and cell-to-cell variability in the componentry of the network. Basal activity is the propensity for activation of the network output in the absence of the signal of interest. We show, using theoretical models of protein kinase signaling, that the combined effect of the two types of noise makes information transfer by such networks highly vulnerable to the loss of negative feedback. In an experimental study of ERK signaling by single cells with heterogeneous ERK expression levels, we verify our theoretical prediction: In the presence of basal network activity, negative feedback substantially increases information transfer to the nucleus by both preventing a near-flat average response curve and reducing sensitivity to variation in substrate expression levels. The interplay between basal network activity, heterogeneity in network componentry, and feedback is thus critical for the effectiveness of protein kinase signaling. Basal activity is widespread in signaling systems under physiological conditions, has phenotypic consequences, and is often raised in disease. Our results reveal an important role for negative feedback mechanisms in protecting the information transfer function of saturable, heterogeneous cell signaling systems from basal activity.cell sensing | MAPK signaling | mutual information | ultrasensitivity | biomolecular networks C ells must sense extracellular concentrations and transfer the information contained about their environment reliably to make appropriate decisions. Understanding the process of information transfer from the biological environment to the nucleus (1) and studying quantitatively how information about the signal is lost along the way are essential in understanding cellular decision-making (2, 3). The signal transduction networks used by cells are subject to various sources of noise, and we are only beginning to explore how these affect the process of information transfer (4, 5). Here we focus, in the context of protein kinase (PK) signaling, on the little-studied effects of two important types of biological noise: cell-to-cell variability in the componentry of the network and basal network activity. The effect on information transfer of cell-to-cell variation (heterogeneity) in the protein componentry of signaling networks remains largely unexplored. Such variation is expected under physiological conditions (6) and underlies the variable responses observed for genetically identical cells exposed to the same stimulus or drug treatment (7-9). By basal activity, we mean the propensity for activation of the signaling system in the absence of the stimulus or signal of interest. Basal activity is widespread in signaling system...

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“…In the pathways controlling mating and osmotic stress responses, basal signalling has been shown to be permanently restricted by a negative feedback loop, which is dependent on the catalytic activity of their own MAPK [37]. Mathematical modelling of this phenomenon suggests that attenuation of an otherwise high basal signal by a negative feedback may be a common trend in MAPK pathways, allowing a fast response and high sensitivity to environmental changes.…”

Section: Wiring Backwards: Phosphorylation-based Feedback Loops In Yementioning

confidence: 99%

Fine regulation of Saccharomyces cerevisiae MAPK pathways by post‐translational modifications

Molina

Cid

Martı́n

2010

Yeast

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Saccharomyces cerevisiae has been widely used as a model eukaryotic organism to elucidate the molecular mechanisms that operate upon activation of signalling pathways. For over two decades, many clues to the regulation of mitogen-activated protein kinase (MAPK) pathways have derived from basic research in yeast. Here we review aspects of MAPK pathway fine-tuning, such as the functional implication of feedback loops or regulatory inputs from other pathways, mediated by post-transcriptional modifications on their components. The impact of recent phosphoproteomic approaches in this particular field is also discussed.

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Dynamic Signaling in the Hog1 MAPK Pathway Relies on High Basal Signal Transduction

Cited by 126 publications

References 38 publications

Differential Role of HAMP-like Linkers in Regulating the Functionality of the Group III Histidine Kinase DhNik1p

Differential Role of HAMP-like Linkers in Regulating the Functionality of the Group III Histidine Kinase DhNik1p

Information transfer by leaky, heterogeneous, protein kinase signaling systems

Fine regulation of Saccharomyces cerevisiae MAPK pathways by post‐translational modifications

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