FLT3 signaling in hematopoietic cells involves CBL, SHC and an unknown P115 as prominent tyrosine-phosphorylated substrates
FLT3 signaling in hematopoietic cells involves CBL, SHC and an unknown P115 as prominent tyrosine-phosphorylated substrates
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DOI：
10.1038/sj.leu.2400921
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发表时间：
1998-03-01
期刊：
影响因子：
11.4
通讯作者：
Rosnet, O
中科院分区：
文献类型：
--
作者：
Lavagna-Sévenier, C;Marchetto, S;Rosnet, O
造血祖细胞的增殖和存活部分依赖于Flt3受体酪氨酸激酶(RTK)与其配体FL之间的相互作用。这种生物学功能主要依赖于启动几个转导级联反应的细胞靶标的酪氨酸磷酸化。当特定的磷酸酶被激活时，这些事件恢复到它们的基础水平。我们分析了表达内源性Flt3的不同造血来源的人细胞系(即单核细胞系、单核细胞系、前B系和原B系)对FL的酪氨酸磷酸化反应，本研究旨在确定(1)在生理相关细胞中Flt3下游底物的同一性，(2)髓系或早期B细胞中不同的底物参与。两个重要的酪氨酸磷酸化蛋白在髓系细胞系中是p52(SHC)和p115(CBL)，在早期B细胞系中是p52(SHC)和一个未鉴定的p115。在FL刺激后，CBL的磷酸化和与磷脂酰肌醇3‘激酶P85亚单位的复合体的形成都随之增加。相反，在未刺激的细胞中观察到的Grb2/CBL结合在刺激后没有改变，在抗CBL免疫沉淀物中从未检测到SHC，FL诱导的CBL与CRKII接头分子的结合也被证明。本研究展示了人造血细胞内源性Flt3受体激活所触发的信号事件，包括B细胞特异性Flt3底物的存在。
Proliferation and survival of hematopoietic progenitors are partially dependent on the interaction between the FLT3 receptor tyrosine kinase (RTK) and its ligand, FL. This biological function depends primarily on tyrosine phosphorylation of cellular targets that initiate several transduction cascades. These events return to their basal levels upon activation of specific phosphatases. We analyzed tyrosine phosphorylation events in response to FL, in human cell lines of different hematopoietic origins that express endogenous FLT3, namely the myelomonocytic, monocytic, pre-B and pro-B lineages, This study aimed at determining (I) the identity of FLT3 downstream substrates in physiologically relevant cells and (2) distinct substrate involvement in myeloid or early B cells. The two prominent tyrosine-phosphorylated proteins are p52(SHC) and p115(CBL) in myeloid cell lines and p52(SHC) and an uncharacterized p115 in early B cell lines. Following FL stimulation, a concomitant increase in both CBL phosphorylation and complex formation with p85 subunit of phosphatidylinositol 3' kinase is observed. In contrast, the GRB2/CBL association observed in unstimulated cells is not modified after stimulation, and SHC is never detected in anti-CBL immunoprecipitates, FL-inducible binding of CBL to the CRKII adaptor molecule is also demonstrated, This study presents a picture of the signaling events triggered by activation of endogenous FLT3 receptor in human hematopoietic cells, including the existence of a B cell-specific FLT3 substrate.