Quantitative analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells.
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.
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, Milan 20139, Italy.
Fabrizio
F
Capuani
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, Milan 20139, Italy.
Alexia
A
Conte
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, Milan 20139, Italy.
Elisabetta
E
Argenzio
The Microsoft Research-University of Trento Centre for Computational and Systems Biology (COSBI), Piazza Manifattura 1, Rovereto (TN) 38068, Italy.
Luca
L
Marchetti
The Microsoft Research-University of Trento Centre for Computational and Systems Biology (COSBI), Piazza Manifattura 1, Rovereto (TN) 38068, Italy.|Dipartimento di Matematica, Università di Trento, Via Sommarive 14, Povo 38100, Italy.
Corrado
C
Priami
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, Milan 20139, Italy.|Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via di Rudinì 8, Milan 20122, Italy.
Simona
http://orcid.org/0000-0001-5536-9399
S
Polo
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, Milan 20139, Italy.|Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via di Rudinì 8, Milan 20122, Italy.|Istituto Europeo di Oncologia, Via Ripamonti 435, Milan 20141, Italy.
Pier Paolo
PP
Di Fiore
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, Milan 20139, Italy.
Sara
S
Sigismund
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, Milan 20139, Italy.
Andrea
A
Ciliberto
D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D003720:Densitometry; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D004815:Epidermal Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; C512478:EGFR protein, human; D066246:ErbB Receptors