The activation loop tyrosine 823 is essential for the transforming capacity of the c-Kit oncogenic mutant D816V

摘要: Oncogenic c-Kit mutations have been shown to display ligand-independent receptor activation and cell proliferation. A substitution of aspartate valine at amino acid 816 (D816V) is one the most commonly found oncogenic in >90% cases mastocytosis less germ-cell tumors, core-binding factor acute myeloid leukemia mucosal melanomas. The mechanisms by which this mutation leads constitutive transformation are not fully understood. Previous studies that D816V causes a structural change loop (A-loop), resulting weaker binding A-loop juxtamembrane domain. In paper, we investigated role Y823, only tyrosine residue A-loop, its c-Kit/D816V introducing Y823F mutation. Although dispensable for kinase activity c-Kit/D816V, presence Y823 was crucial proliferation survival. Furthermore, selectively downregulates Ras/Erk Akt pathways as well phosphorylation STAT5 reduces transforming capacity D816V/c-Kit vitro. We further show mice injected with cells expressing c-Kit/D816V/Y823F significantly reduced tumor size weight compared controls. Finally, microarray analysis, comparing Y823F/D816V demonstrate upregulation proapoptotic genes, whereas genes survival downregulated. Thus, necessary activation, but essential ability mutant.