M-COPA suppresses endolysosomal Kit-Akt oncogenic signalling through inhibiting the secretory pathway in neoplastic mast cells

摘要: Gain-of-function mutations in Kit receptor tyrosine kinase result the development of a variety cancers, such as mast cell tumours, gastrointestinal stromal tumours (GISTs), acute myeloid leukemia, and melanomas. The drug imatinib, selective inhibitor Kit, is used for treatment mutant Kit-positive cancers. However, domain, which are frequently found neoplastic cells, confer an imatinib resistance, cancers expressing mutants can proliferate presence imatinib. Recently, we showed that cells endogenously express imatinib-resistant mutant, causes oncogenic activation phosphatidylinositol 3-kinase-Akt (PI3K-Akt) pathway signal transducer activator transcription 5 (STAT5) but only on endolysosomes endoplasmic reticulum (ER), respectively. Here, show strategy inhibition Kit-PI3K-Akt by M-COPA (2-methylcoprophilinamide), this secretory pathway. In M-COPA-treated localization ER significantly increased, whereas endolysosomal disappears, indicating blocks biosynthetic transport from ER. greatly inhibits Akt without affecting association with PI3K, ER-localized Kit-PI3K complex unable to activate Akt. Importantly, not suppresses proliferation through inhibiting anti-apoptotic activation. Results our assay Erk also other compartments. Furthermore, Tyr568/570, Tyr703, Tyr721, Tyr936 phosphorylated ER, these five residues all before reaches plasma membrane (PM). Our study provides evidence tyrosine-phosphorylated soon after synthesis demonstrates efficacious growth suppression cells.