The epidermal growth factor receptor (EGFR)-S442F mutant displays increased affinity for neuregulin-2β and agonist-independent coupling with downstream signalling events

• Published in: Biochemical journal Vol. 396; no. 1; pp. 79 - 88
• Main Authors: Gilmore, Jennifer L., Gallo, Richard M., Riese, David J.
• Format: Journal Article
• Language: English
• Published: Portland Press Ltd 15.05.2006
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/BJ20051687

The EGFR (epidermal growth factor receptor; ErbB1) is frequently the subject of genetic changes in human tumours which contribute to the malignant phenotype by altering EGFR signalling. Examples of such genetic changes include overexpression, extracellular domain deletions and point mutations, and small deletions in the tyrosine kinase domain. We hypothesized that a point mutation in one of the EGFR ligand-binding domains would increase the affinity of EGFR for NRG2β (neuregulin-2β), which is not a potent stimulus of signalling by EGFR-Wt (wild-type EGFR). This mutation would permit NRG2β stimulation of EGFR signalling in settings in which NRG2β does not normally do so. To test this hypothesis, we have generated and evaluated various EGFR alleles containing mutations at Val441 and Ser442. NRG2β is a much more potent stimulus of the EGFR-S442F mutant than of EGFR-Wt. Furthermore, the affinity of NRG2β for the EGFR-S442F mutant is greater than the affinity of NRG2β for EGFR-Wt. Finally, the EGFR-S442F mutant constitutively suppresses apoptosis via phosphoinositide 3-kinase and Akt signalling but is not highly tyrosine phosphorylated in the absence of ligand. These results suggest that mutations in the EGFR ligand-binding domain in tumours may permit potent stimulation of EGFR signalling by ligands that are not normally potent EGFR agonists, thereby providing for a novel mechanism by which EGFR signalling may be deregulated. These results also suggest that novel EGFR mutations and signalling activities may be responsible for deregulated EGFR signalling in tumour cells.