Format

Send to

Choose Destination
See comment in PubMed Commons below
Nat Commun. 2015 Aug 12;6:7999. doi: 10.1038/ncomms8999.

Quantitative analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells.

Author information

1
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, Milan 20139, Italy.
2
The Microsoft Research-University of Trento Centre for Computational and Systems Biology (COSBI), Piazza Manifattura 1, Rovereto (TN) 38068, Italy.
3
1] The Microsoft Research-University of Trento Centre for Computational and Systems Biology (COSBI), Piazza Manifattura 1, Rovereto (TN) 38068, Italy [2] Dipartimento di Matematica, Università di Trento, Via Sommarive 14, Povo 38100, Italy.
4
1] IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, Milan 20139, Italy [2] Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via di Rudinì 8, Milan 20122, Italy.
5
1] IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, Milan 20139, Italy [2] Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via di Rudinì 8, Milan 20122, Italy [3] Istituto Europeo di Oncologia, Via Ripamonti 435, Milan 20141, Italy.

Abstract

Ubiquitination of the epidermal growth factor receptor (EGFR) that occurs when Cbl and Grb2 bind to three phosphotyrosine residues (pY1045, pY1068 and pY1086) on the receptor displays a sharp threshold effect as a function of EGF concentration. Here we use a simple modelling approach together with experiments to show that the establishment of the threshold requires both the multiplicity of binding sites and cooperative binding of Cbl and Grb2 to the EGFR. While the threshold is remarkably robust, a more sophisticated model predicted that it could be modulated as a function of EGFR levels on the cell surface. We confirmed experimentally that the system has evolved to perform optimally at physiological levels of EGFR. As a consequence, this system displays an intrinsic weakness that causes--at the supraphysiological levels of receptor and/or ligand associated with cancer--uncoupling of the mechanisms leading to signalling through phosphorylation and attenuation through ubiquitination.

PMID:
26264748
PMCID:
PMC4538861
DOI:
10.1038/ncomms8999
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center