| Co-Investigator(Kenkyū-buntansha) |
MIZUKI Masao Osaka University, Graduate School Of Medicine, Assistant Professor, 医学系研究科, 助手 (80283761)
MATSUMURA Itaru Osaka University, Graduate School Of Medicine, Lecturer, 医学系研究科, 講師 (00294083)
KANAKURA Yuzuru Osaka University, Graduate School Of Medicine, Professor, 医学系研究科, 教授 (20177489)
SHIBAYAMA Hirohiko Osaka University, Graduate School Of Medicine, Assistant Professor, 医学系研究科, 助手 (60346202)
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| Research Abstract |
l. Cytoplasmic tyrosine residues involved in KIT-signal transduction
We analyzed effects of phenylalanine conversion of 22 tyrosine residues in the cytoplasmic domain on KIT-mediated cell function. In the wild type KIT, although the proliferation and survival was not affected by these Tyr->Phe conversions, the conversions of Tyr 567, 569, or 719 suppressed the cell migration mediated by KIT/SCF interaction. Tyr567 activated Src family kinase, p38 MAPkinase, which induced Ca2+ influx and the subsequent activation of Erk. Tyr 719 activated PI3-kinase, which induced Ca2+ influx. Both pathways synergistically induced the cell migration. In the constitutively active KIT mutant of kinase domain, Phe conversion of Tyr 719 abolished the kinase activity and the proliferative activity, which suggested that Tyr 719 and associated PI3-kinase is critical for kinase and transforming activity.
2. Targeting inhibition of constitutive active KITTyrosine kinase inhibitors, STI571 and AG1296 suppressed the kinase activity of juxtamembrane domain KIT mutant more effectively than wild type. In contrast, kinase domain mutant resisted to these inhibitors, even though in combination. Therefore, the sensitivity to the inhibitor differs dependent on the type of mutant.
3. FIt3 mutation specific target genes Microchip analysis revealed that Flt3 internal tandem duplication (Flt3-ITD) mutation specifically induced STAT3/5 target genes such as pim-2, SOCS3 and CIS. Flt3-ITD specifically suppressed myeloid-specific transcription factors such as C/EBPalpha and Pu. 1, which suggested that Flt3-ITD is involved in the differentiation block in AML.
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