Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

The long and short of cell signaling

02.08.2010
By bolstering a sophisticated computational model with quantitative experimental data, researchers begin to decipher the workings of a complex signaling network

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 information

1. 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
Further information:
http://www.rikenresearch.riken.jp/eng/research/6350
http://www.researchsea.com

More articles from Life Sciences:

nachricht Nesting aids make agricultural fields attractive for bees
20.07.2017 | Julius-Maximilians-Universität Würzburg

nachricht The Kitchen Sponge – Breeding Ground for Germs
20.07.2017 | Hochschule Furtwangen

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

Im Focus: The proton precisely weighted

What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.

To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...

Im Focus: On the way to a biological alternative

A bacterial enzyme enables reactions that open up alternatives to key industrial chemical processes

The research team of Prof. Dr. Oliver Einsle at the University of Freiburg's Institute of Biochemistry has long been exploring the functioning of nitrogenase....

Im Focus: The 1 trillion tonne iceberg

Larsen C Ice Shelf rift finally breaks through

A one trillion tonne iceberg - one of the biggest ever recorded -- has calved away from the Larsen C Ice Shelf in Antarctica, after a rift in the ice,...

Im Focus: Laser-cooled ions contribute to better understanding of friction

Physics supports biology: Researchers from PTB have developed a model system to investigate friction phenomena with atomic precision

Friction: what you want from car brakes, otherwise rather a nuisance. In any case, it is useful to know as precisely as possible how friction phenomena arise –...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

The technology with a feel for feelings

12.07.2017 | Event News

Leipzig HTP-Forum discusses "hydrothermal processes" as a key technology for a biobased economy

12.07.2017 | Event News

 
Latest News

Researchers create new technique for manipulating polarization of terahertz radiation

20.07.2017 | Information Technology

High-tech sensing illuminates concrete stress testing

20.07.2017 | Materials Sciences

First direct observation and measurement of ultra-fast moving vortices in superconductors

20.07.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>