Autophosphorylation of the carboxyl-terminal domain is not required for oncogenic transformation by lung-cancer derived EGFR mutants

International Journal of Cancer. Journal International Du Cancer
Jeonghee ChoMatthew Meyerson

Abstract

Aberrant activation of cancer-derived mutants of the epidermal growth factor receptor (EGFR) is closely associated with cancer pathogenesis and is thought to be mediated through multiple tyrosine phosphorylations within the C-terminal domain. Here, we examined the consequences of the loss of these C-terminal phosphorylation sites on cellular transformation in the context of lung-cancer-derived L858R, exon 19 deletion and exon 20 insertion mutant EGFR. Oncogenic EGFR mutants with substitution of the 10 potential C-terminal tyrosine autophosphorylation sites for phenylalanine (CYF10) were still able to promote anchorage-independent growth in soft agar at levels comparable to the parental L858R or exon19 deletion or exon 20 insertion mutants with intact autophosphorylation sites. Furthermore, these CYF10 mutants retained the ability to transform Ba/F3 cells in the absence of IL-3. Bead-based phosphorylation and immunoprecipitation analyses demonstrated that key EGFR-associated proteins-including Grb2 and PLC-γ-are neither phosphorylated nor bound to CYF10 mutants in transformed cells. Taken together, we conclude that tyrosine phosphorylation is not required for oncogenic activity of lung-cancer-derived mutant EGFR, suggesting thes...Continue Reading

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