Strong negative feedback from Erk to Raf confers robustness to MAPK signalling

Fritsche‐Guenther, Raphaela; Witzel, Franziska; Sieber, Anja; Herr, Ricarda; Schmidt, Nadine; Braun, Sandra; Brummer, Tilman; Sers, Christine; Blüthgen, Nils

doi:10.1038/msb.2011.27

Cited by 182 publications

(224 citation statements)

References 58 publications

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“…In sum, here we found that post-transcriptional control of a master transcriptional regulator provides an efficient mechanism that assures canalized development and that stabilizes a transcriptional network during development and in adult animals. The role of post-transcriptional control in stabilizing the activities and levels of key activators of systems based on feedback loops has been previously proposed 46,47,51 , but to the best of our knowledge, our work constitutes the first theoretical and experimental example of this control principle.…”

Section: Discussionmentioning

confidence: 84%

“…It has been previously suggested that post-transcriptional control (for example, by miRNAs) could be used to diminish variability in biological systems [46][47][48][49][50][51] . In this context, we speculate that the high-transcriptional/high-turnover Clk profile stabilizes the circadian system by minimizing the consequences of transcriptional noise and/or by allowing rapid transcriptional feedback control.…”

Section: Resultsmentioning

confidence: 99%

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Clk post-transcriptional control denoises circadian transcription both temporally and spatially

et al. 2015

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The transcription factor CLOCK (CLK) is essential for the development and maintenance of circadian rhythms in Drosophila. However, little is known about how CLK levels are controlled. Here we show that Clk mRNA is strongly regulated post-transcriptionally through its 3 0 UTR. Flies expressing Clk transgenes without normal 3 0 UTR exhibit variable CLK-driven transcription and circadian behaviour as well as ectopic expression of CLK-target genes in the brain. In these flies, the number of the key circadian neurons differs stochastically between individuals and within the two hemispheres of the same brain. Moreover, flies carrying Clk transgenes with deletions in the binding sites for the miRNA bantam have stochastic number of pacemaker neurons, suggesting that this miRNA mediates the deterministic expression of CLK. Overall our results demonstrate a key role of Clk post-transcriptional control in stabilizing circadian transcription, which is essential for proper development and maintenance of circadian rhythms in Drosophila.

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Section: Discussionmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Clk post-transcriptional control denoises circadian transcription both temporally and spatially

et al. 2015

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“…Although both oncogenes activate the MAPK cascade, differences also exist: first, KRAS activates a number of further signal transducers in addition to BRAF, 43 and second, oncogenic KRAS, but not BRAF, is subject to strong additional feedback control within the MAPK cascade. 44 These differences may explain why BRAF-mutated tumors have distinct molecular features and therapeutic profiles compared with BRAF non-mutated tumors, including those that are KRAS mutated. 3 Similar to BRAF, oncogenic KRAS can also initiate serrated lesions in the mouse, 45 but in contrast to BRAF, tumor progression in KRAS-transgenic mice crucially depends on loss of the tumor-suppressor Ink4a/ARF, but not on Wnt/β-catenin activation.…”

Section: Discussionmentioning

confidence: 99%

“…Caco2-tet cells have previously been modified to express a second-generation tetracycline-regulated transactivator and transcriptional silencer. 44,55 Caco2-tet were transfected using Lipofectamine 2000 (Life Technologies, Darmstadt, Germany) as per the manufacturer's instructions, using tetracyclineinducible plasmids coding for GFP, or combinations of GFP with BRAF V600E or BRAF V600K . We used luciferase reporter constructs with multimerized ELK, FOXO3 or LEF/TCF sites.…”

Section: Cell Culturementioning

confidence: 99%

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

et al. 2014

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Colon cancer cells frequently carry mutations that activate the β-catenin and mitogen-activated protein kinase (MAPK) signaling cascades. Yet how oncogenic alterations interact to control cellular hierarchies during tumor initiation and progression is largely unknown. We found that oncogenic BRAF modulates gene expression associated with cell differentiation in colon cancer cells. We therefore engineered a mouse with an inducible oncogenic BRAF transgene, and analyzed BRAF effects on cellular hierarchies in the intestinal epithelium in vivo and in primary organotypic culture. We demonstrate that transgenic expression of oncogenic BRAF in the mouse strongly activated MAPK signal transduction, resulted in the rapid development of generalized serrated dysplasia, but unexpectedly also induced depletion of the intestinal stem cell (ISC) pool. Histological and gene expression analyses indicate that ISCs collectively converted to short-lived progenitor cells after BRAF activation. As Wnt/β-catenin signals encourage ISC identity, we asked whether β-catenin activity could counteract oncogenic BRAF. Indeed, we found that intestinal organoids could be partially protected from deleterious oncogenic BRAF effects by Wnt3a or by small-molecule inhibition of GSK3β. Similarly, transgenic expression of stabilized β-catenin in addition to oncogenic BRAF partially prevented loss of stem cells in the mouse intestine. We also used BRAF V637E knock-in mice to follow changes in the stem cell pool during serrated tumor progression and found ISC marker expression reduced in serrated hyperplasia forming after BRAF activation, but intensified in progressive dysplastic foci characterized by additional mutations that activate the Wnt/β-catenin pathway. Our study suggests that oncogenic alterations activating the MAPK and Wnt/β-catenin pathways must be consecutively and coordinately selected to assure stem cell maintenance during colon cancer initiation and progression. Notably, loss of stem cell identity upon induction of BRAF/MAPK activity may represent a novel fail-safe mechanism protecting intestinal tissue from oncogene activation.

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“…Negative feedback is a common feature of PK signaling systems. For example, activated ERK inhibits Raf by phosphorylation (30), and ligandinduced phosphatases (e.g., MAPK phosphatases and Sprouty proteins) negatively regulate MAPK activation (31,32). In this paper, we argue that negative feedback protects information transfer by these systems from the combined effects of basal activity and cell-to-cell variation in network componentry.…”

Section: Loss Of Negative Feedback Can Eradicate Information Transfer Bymentioning

confidence: 93%

Information transfer by leaky, heterogeneous, protein kinase signaling systems

Voliotis¹,

Perrett

McWilliams³

et al. 2014

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

121

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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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Strong negative feedback from Erk to Raf confers robustness to MAPK signalling

Abstract: This study shows that MAPK signalling is robust against protein level changes due to a strong negative feedback from Erk to Raf. Surprisingly, robustness is provided through a fast post-translational mechanism although variation of Erk levels occurs on a timescale of days.

Cited by 182 publications

References 58 publications

Clk post-transcriptional control denoises circadian transcription both temporally and spatially

Clk post-transcriptional control denoises circadian transcription both temporally and spatially

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

Information transfer by leaky, heterogeneous, protein kinase signaling systems

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