THE ENHANCED TUMORIGENIC ACTIVITY OF A MUTANT EPIDERMAL GROWTH-FACTORRECEPTOR COMMON IN HUMAN CANCERS IS MEDIATED BY THRESHOLD LEVELS OF CONSTITUTIVE TYROSINE PHOSPHORYLATION AND UNATTENUATED SIGNALING

Deregulation of signaling by the epidermal growth factor receptor (EGF R) is common in human malignancy progression. One mutant EGFR (various ly named Delta EGFR, de2-7 EGFR, or EGFRvIII), which occurs frequently in human cancers, lacks a portion of the extracellular ligand-binding domain due to genomic deletions that eliminate exons 2 to 7 and confe rs a dramatic enhancement of brain tumor cell tumorigenicity in vivo. In order to dissect the molecular mechanisms of this activity, we anal yzed location, autophosphorylation, and attenuation of the mutant rece ptors. The mutant receptors were expressed on the cell surface and con stitutively autophosphorylated at a significantly decreased level comp ared with wild-type EGFR activated by ligand treatment. Unlike wild-ty pe EGFR, the constitutively active Delta EGFR were not down-regulated, suggesting that the altered conformation of the mutant did not result in exposure of receptor sequence motifs required for endocytosis and lysosomal sorting. Mutational analysis showed that the enhanced tumori genicity was dependent on intrinsic tyrosine kinase activity and was m ediated through the carboxyl terminus. In contrast with wild-type rece ptor, mutation of any major tyrosine autophosphorylation site abolishe d these activities suggesting that the biological functions of Delta E GFR are due to low constitutive activation with mitogenic effects ampl ified by failure to attenuate signaling by receptor down-regulation.