Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD
Publication in refereed journal

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其它資訊
摘要The type III receptor tyrosine kinase FLT3 is frequently mutated in acute myeloid leukemia. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. The position of this tyrosine residue is well conserved in all receptor tyrosine kinases. It has been reported that phosphorylation of the activation loop tyrosine is critical for catalytic activity for some but not all receptor tyrosine kinases. The role of Y842 residue in FLT3 signaling has not yet been studied. In this report, we show that Y842 is not important for FLT3 activation or ubiquitination but plays a critical role in regulating signaling downstream of the receptor as well as controlling receptor stability. We found that mutation of Y842 in the FLT3-ITD oncogenic mutant background reduced cell viability and increased apoptosis. Furthermore, the introduction of the Y842 mutation in the FLT3ITD background led to a dramatic reduction in in vitro colony forming capacity. Additionally, mice injected with cells expressing FLT3-ITD/Y842F displayed a significant delay in tumor formation, compared to FLT3-ITD expressing cells. Microarray analysis comparing gene expression regulated by FLT3-ITD versus FLT3-ITD/Y842F demonstrated that mutation of Y842 causes suppression of anti-apoptotic genes. Furthermore, we showed that cells expressing FLT3-ITD/Y842F display impaired activity of the RAS/ERK pathway due to reduced interaction between FLT3 and SHP2 leading to reduced SHP2 activation. Thus, we suggest that Y842 is critical for FLT3-mediated RAS/ERK signaling and cellular transformation.
著者KAZI JU, CHOUGULE RA, LI TF, SU XW, MOHARRAM SA, RUPAR K, MARHALL A, GAZI M, SUN JM, ZHAO H, RONNSTRAND L
期刊名稱Cellular and Molecular Life Sciences
出版年份2017
月份7
卷號74
期次14
出版社Springer
頁次2679 - 2688
國際標準期刊號1420-682X
電子國際標準期刊號1420-9071
語言英式英語
關鍵詞FLT3,FLT3-ITD,Activation loop,Acute myeloid leukemia,SHP2,Transformation,Survival,Microarray
Web of Science 學科類別Biochemistry & Molecular Biology;Cell Biology;Biochemistry & Molecular Biology;Cell Biology

上次更新時間 2021-19-01 於 02:26