Regulation of EGFR signal transduction by analogue-to-digital conversion in endosomes

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Abstract

An outstanding question is how receptor tyrosine kinases (RTKs) determine different cell-fate decisions despite sharing the same signalling cascades. Here, we uncovered an unexpected mechanism of RTK trafficking in this process. By quantitative high-resolution FRET-microscopy we found that phosphorylated epidermal growth factor receptor (p-EGFR) is not randomly distributed but packaged at constant mean amounts in endosomes. Cells respond to higher EGF concentrations by increasing the number of endosomes but keeping the mean p-EGFR content per endosome almost constant. By mathematical modelling we found that this mechanism confers both robustness and regulation to signalling output. Different growth factors caused specific changes in endosome number and size in various cell systems and changing the distribution of p-EGFR between endosomes was sufficient to reprogram cell-fate decision upon EGF stimulation. We propose that the packaging of p-RTKs in endosomes is a general mechanism to ensure the fidelity and specificity of the signalling response.

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Roberto Villaseñor

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

Competing interests
The authors declare that no competing interests exist.
Hidenori Nonaka

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

Competing interests
The authors declare that no competing interests exist.
Perla Del Conte-Zerial

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

Competing interests
The authors declare that no competing interests exist.
Yannis Kalaidzidis

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

Competing interests
The authors declare that no competing interests exist.
Marino Zerial

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

For correspondence
zerial@mpi-cbg.de

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal studies were conducted in accordance with German animal welfare legislation and in strict pathogen-free conditions in the animal facility of the Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany. Protocols were approved by the Institutional Animal Welfare Officer (Tierschutzbeauftragter) under the license Anzeige der Tötung von Tieren zu wissenschaftlichen Zwecken AZ: 24-9168.24-9/2009-1 (valid from 2009 until 31.12.2012) and AZ: 24-9168.24-9/2012-1(valid from 30.4.2012 through 30.4.2015), obtained from the regional Ethical Commission for Animal Experimentation of Dresden, Germany (Tierversuchskommission, Landesdirektion Dresden).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.