Effects of endoplasmic reticulum stressors on maturation and signaling of hemizygous and heterozygous wild-type and mutant forms of KIT

摘要: Gain of function mutations KIT are frequent in some human tumors, and sensible to tyrosine kinase inhibitors. In most oncogenic heterozygous, however vitro data activation have been obtained with hemizygous mutation. This study aimed investigate the maturation wild-type (WT) mutant (M) forms heterozygous conditions. WT two types exon 11 deletions M were expressed NIH3T3 cell lines. Membrane expression was quantified by flow cytometry. Quantification glycosylated phosphorylated AKT ERK performed western blot. Simultaneous treatment endoplasmic reticulum (ER) inhibitors, tunicamycin or brefeldin A induced a complete inhibition membrane 145 kDa form KIT. By contrast ER inhibitors alone, only partly inhibited this form. also activation-dependent phosphorylation ERK1/2. Brefeldin down regulation M, an intra-cellular accumulation 125 but not M. Heterozygous cells had glycosylation response patterns more similar than Phosphorylated reduced comparison cells, presence all Effects significantly different mutants. Differences trafficking result differences downstream signaling pathways, PI3K/AKT pathway appears be tied mature at surface.