The Enhanced Tumorigenic Activity of a Mutant Epidermal Growth Factor Receptor Common in Human Cancers Is Mediated by Threshold Levels of Constitutive Tyrosine Phosphorylation and Unattenuated Signaling

• DOI: 10.1074/jbc.272.5.2927
• Publication Date: 2002-07-26T14:57:46Z
• Authors: H.-J. Su Huang; Motoo Nagane; Candice K. Klingbeil; Hong Lin; Ryo Nishikawa; Xiang-Dong Ji; Chun-Ming Huang; Gordon N. Gill; H. Steven Wiley; Webster K. Cavenee
• Keywords: 0301 basic medicine; Base Sequence; Epidermal Growth Factor; Brain Neoplasms; Molecular Sequence Data; Down-Regulation; Mice, Nude; Endocytosis; Peptide Fragments; Recombinant Proteins; Cell Line; 3. Good health; ErbB Receptors; Mice; 03 medical and health sciences; Mutagenesis, Site-Directed; Animals; Humans; Amino Acid Sequence; Phosphorylation; Glioblastoma; Phosphotyrosine; DNA Primers

Deregulation of signaling by the epidermal growth factor receptor (EGFR) is common in human malignancy progression. One mutant EGFR (variously named ΔEGFR, de2-7 EGFR, or EGFRvIII), which occurs frequently cancers, lacks a portion extracellular ligand-binding domain due to genomic deletions that eliminate exons 2 7 and confers dramatic enhancement brain tumor cell tumorigenicity <i>in vivo</i>. In order dissect molecular mechanisms this activity, we analyzed location, autophosphorylation, attenuation receptors. The receptors were expressed on surface constitutively autophosphorylated at significantly decreased level compared with wild-type activated ligand treatment. Unlike active ΔEGFR not down-regulated, suggesting altered conformation did result exposure sequence motifs required for endocytosis lysosomal sorting. Mutational analysis showed enhanced was dependent intrinsic tyrosine kinase activity mediated through carboxyl terminus. contrast receptor, mutation any major autophosphorylation site abolished these activities biological functions are low constitutive activation mitogenic effects amplified failure attenuate down-regulation.