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

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.

Emerging functions of the EGFR in cancer

“…In particular, heterodimers with the ligand‐orphan receptor ErbB2 are constitutively active, evade receptor ubiquitination and degradation, and are mostly recycled back to the PM, thereby producing sustained signaling and cell proliferation (Mellman and Yarden, ; Schneider and Yarden, ). In agreement, saturation of the endocytic and/or the ubiquitination machinery has been proposed as a mechanism underlying sustained signaling in EGFR‐overexpressing cancer cells (Capuani et al ., ; French et al ., ; Wiley, ).…”

Optimization Algorithms for Computational Systems Biology

“…This problem is often formulated in the form of least squares, as in models related to diabetes [10,19,20], biological pathways [21][22][23][24], and pharmacokinetics/pharmacodynamics [25,26]. Least squares problems may arise in statistical regression as well [27][28][29][30][31][32].…”

Dysregulation and detection methods of EGFR in oral cancer. A narrative review.

“…47 There are several molecular techniques with variable specificities and sensitivities for detecting EGFR in oral mucosa and its association with various events in OSCC, (Table I). 3,9,17,19,20,27,28,31,34,35,38,39,41,45,47,48 The most widely used method for EGFR detection is IHC. It is a simple and relatively quick technique.…”

“…Polymerase chain reaction (PCR) has been used to detect EGFR mutations in normal and neoplastic tissues. 3,17,31,35,49 In oral cancer specific tests to evaluate deletions, silent mutations or changes at amino acid level encoded in exons 18 to 21 have been used. 33 Bagan et al 26 studied the genomic amplification of EGFR in frozen tissue samples.…”

“…34,35 Yang et al 36 suggested that the ability of mutated EGFR to escape downregulation may be due to lack of: ubiquitin binding, dysregulation of kinase associated with cyclin-G, and reduced levels of CD82 (metastasis suppressor). Zhen et al 34 studied the effect of curcumin on cultivate cells from patients diagnosed with OSCC.…”