Like a telegraph transmission, the significance of a cellular signal can change greatly depending on whether it arrives as a brief ‘dot’ or a sustained ‘dash’. For example, transient activation of extracellular receptor kinase 1/2 (ERK) by epidermal growth factor (EGF) causes cells to divide, while prolonged ERK activation induced by heregulin (HRG) instructs these same cells to differentiate.
Cell biologists have struggled to untangle the relationship between this signaling network and cell fate, but a collaborative effort between Mariko Okada-Hatakeyama at the RIKEN Center for Allergy and Immunology in Yokohama and Boris Kholodenko at University College Dublin in Ireland has achieved an important breakthrough by pairing quantitative experiments with computational modeling1.
Okada-Hatakeyama’s team previously examined the expression of c-fos, a so-called ‘immediate early gene’ whose expression is induced shortly following ERK activation, and obtained somewhat contradictory findings2. ”Early gene expression time-course profiles were the same regardless of whether the upstream ERK signal is transient or sustained,” she says. “However, levels of Fos protein were ‘all or none’ for sustained and transient signals, respectively.”
Based on an initial interpretation of their computational model of this pathway, Okada-Hatakeyama, Kholodenko and colleagues proposed that the effects of both HRG and EGF on c-fos expression were modulated purely by dual-specificity phosphatases (DUSPs), enzymes that inhibit ERK’s capability to induce c-fos. However, experiments with a forced reduction of DUSP in cultured cells did not fully replicate these predictions. “There were long and serious discussions whether [our experiment] was working properly or the model was wrong,” says Okada-Hatakeyama.
This reassessment led to experiments that enabled the researchers to demonstrate the existence of a second, previously unknown mechanism for repression of c-fos expression that is triggered only in response to HRG. Together, these two ERK-activated ‘negative feedback’ systems appropriately control c-fos transcription in the process of cellular differentiation.
In parallel, their model also revealed how the combination of ERK-induced c-fos expression and sustained signaling activity by ERK outside the nucleus lead to steady production of c-Fos protein. This system architecture results in a highly stable signaling arrangement that filters out extraneous background noise and induces all-or-none output, according to Okada-Hatakeyama. “We learned from this study that cells possess very simple but robust system structures that can fight against unwanted perturbations,” she says. “This cellular signaling network is still a ‘black box’ and what we can do [with computational modeling] is very much limited … but we hope to [untangle] the cell decision program someday.”
The corresponding author for this highlight is based at the Laboratory for Cellular Systems Modeling, RIKEN Research Center for Allergy and Immunology
Journal information1. Nakakuki, T., Birtwistle, M.R., Saeki, Y., Yumoto, N., Ide, K., Nagashima, T., Brusch, L., Ogunnaike, B.A., Okada-Hatakeyama, M. & Kholodenko, B.N. Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics. Cell 141, 884–896 (2010)
2. Nagashima, T., Shimodaira, H., Ide, K., Nakakuki, T., Tani, Y., Takahashi, K., Yumoto, N., & Hatakeyama, M. Quantitative transcriptional control of ErbB receptor signaling undergoes graded to biphasic response for cell differentiation. The Journal of Biological Chemistry 282, 4045–4056 (2007)
gro-pr | Research asia research news
Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel
The Nagoya Protocol Creates Disadvantages for Many Countries when Applied to Microorganisms
05.12.2016 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
05.12.2016 | Power and Electrical Engineering
05.12.2016 | Information Technology
05.12.2016 | Earth Sciences