The Mammalian MAPK/ERK Pathway Exhibits Properties of a Negative Feedback Amplifier

Sturm, Oliver; Orton, Richard; Grindlay, Joan; Birtwistle, Marc R.; Vyshemirsky, Vladislav; Gilbert, David; Calder, Muffy; Pitt, Andrew R.; Kholodenko, Boris N.; Kölch, Walter

doi:10.1126/scisignal.2001212

Cited by 230 publications

(323 citation statements)

References 31 publications

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“…To introduce negative feedback, we assume that binding of pSub to either form of the kinase causes its reversible inactivation. We observe a more graded response as a function of the signal in the presence of negative feedback, as has been reported for some other biochemical networks (35)(36)(37), while the threshold value is unchanged (Fig. 1D).…”

Section: Loss Of Negative Feedback Can Eradicate Information Transfer Bysupporting

confidence: 65%

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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Section: Loss Of Negative Feedback Can Eradicate Information Transfer Bysupporting

confidence: 65%

Information transfer by leaky, heterogeneous, protein kinase signaling systems

Voliotis¹,

Perrett

McWilliams³

et al. 2014

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

122

View full text Add to dashboard Cite

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“…These properties have decisive effects on the MAPK cascade drug sensitivity and adaptation to perturbations. In particular, the active ERK concentration was shown to be stabilized in response to drug-induced perturbations of the upstream ERK kinase, MEK (Sturm et al 2010). Yet, above a certain threshold strength, negative feedback can induce damped or sustained oscillations in the system.…”

Section: Intricate Rtk Network Dynamics Are Brought About By Feedbackmentioning

confidence: 99%

“…Using a combination of modeling and validating experiments, it was shown that the integration of a three-tier MAPK cascade structure with negative feedback generates emergent systems properties that resemble the features of a negative feedback amplifier (NFA), known from engineering (Sturm et al 2010). These properties have decisive effects on the MAPK cascade drug sensitivity and adaptation to perturbations.…”

Section: Intricate Rtk Network Dynamics Are Brought About By Feedbackmentioning

confidence: 99%

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Complexity of Receptor Tyrosine Kinase Signal Processing

Volinsky

Kholodenko

2013

Cold Spring Harbor Perspectives in Biology

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Our knowledge of molecular mechanisms of receptor tyrosine kinase (RTK) signaling advances with ever-increasing pace. Yet our understanding of how the spatiotemporal dynamics of RTK signaling control specific cellular outcomes has lagged behind. Systems-centered experimental and computational approaches can help reveal how overlapping networks of signal transducers downstream of RTKs orchestrate specific cell-fate decisions. We discuss how RTK network regulatory structures, which involve the immediate posttranslational and delayed transcriptional controls by multiple feed forward and feedback loops together with pathway cross talk, adapt cells to the combinatorial variety of external cues and conditions. This intricate network circuitry endows cells with emerging capabilities for RTK signal processing and decoding. We illustrate how mathematical modeling facilitates our understanding of RTK network behaviors by unraveling specific systems properties, including bistability, oscillations, excitable responses, and generation of intricate landscapes of signaling activities.

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“…Unexpectedly, the large difference in EGFR activation with low-and high-affinity EGFR ligands did not confer a large difference in downstream signaling to ERK, with only an approximately 5.5-fold EC 50 difference observed between AREG (low-affinity) and EGF (high-affinity). This suggests that the network topology of the EGFR:ERK pathway, previously described as negative feedback amplifier (40), enables robust signal amplification that compensates for the wide differences in EGFR ligand affinities (Fig. 1C).…”

Section: Monoclonal Antibodies Poorly Inhibit High-affinity Egfr Ligandsmentioning

confidence: 99%

Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic

Kearns

Bukhalid

Sevecka

et al. 2015

Molecular Cancer Therapeutics

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Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by highaffinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor-antagonist interactions. Model simulations suggested that an oligoclonal antibody combination may overcome signal amplification within the EGFR:ERK pathway driven by all EGFR ligands. Based on this, we designed MM-151, a combination of three fully human IgG1 monoclonal antibodies that can simultaneously engage distinct, nonoverlapping epitopes on EGFR with subnanomolar affinities. In signaling studies, MM-151 antagonized high-affinity EGFR ligands more effectively than cetuximab, leading to an approximately 65-fold greater decrease in signal amplification to ERK. In cell viability studies, MM-151 demonstrated antiproliferative activity against high-affinity EGFR ligands, either singly or in combination, while cetuximab activity was largely abrogated under these conditions. We confirmed this finding both in vitro and in vivo in a cell line model of autocrine high-affinity ligand expression. Together, these preclinical studies provide rationale for the clinical study of MM-151 and suggest that high-affinity EGFR ligand expression may be a predictive response marker that distinguishes MM-151 from other anti-EGFR therapeutics.

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The Mammalian MAPK/ERK Pathway Exhibits Properties of a Negative Feedback Amplifier

Cited by 230 publications

References 31 publications

Information transfer by leaky, heterogeneous, protein kinase signaling systems

Information transfer by leaky, heterogeneous, protein kinase signaling systems

Complexity of Receptor Tyrosine Kinase Signal Processing

Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic

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