Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl).
Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl).
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DOI：
10.1182/blood-2004-05-1768
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发表时间：
2005
期刊：
影响因子：
20.3
通讯作者：
S. Zeng;Zhiheng Xu;S. Lipkowitz;J. Longley
中科院分区：
文献类型：
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作者：
S. Zeng;Zhiheng Xu;S. Lipkowitz;J. Longley
KIT受体酪氨酸激酶的激活有助于几种人类疾病的发病机制，但调节KIT信号传导的机制尚未完全表征。在这里，我们表明，干细胞因子（SCF），KIT的配体，诱导KIT和Cbl蛋白之间的相互作用和它们的相互降解。在SCF刺激后，KIT结合并诱导Cbl蛋白的磷酸化，Cbl蛋白反过来充当E3连接酶，介导KIT及其自身的泛素化和降解。Cbl的酪氨酸激酶结合和环指结构域对于Cbl介导的KIT的泛素化和降解是必需的。我们提出了一个负反馈回路控制SCF-KIT信号通路，其中SCF激活KIT。活化的KIT进而诱导Cbl蛋白的磷酸化和活化。然后Cbl蛋白结合并指导活化的KIT的降解，导致KIT信号转导的下调。
Activation of the KIT receptor tyrosine kinase contributes to the pathogenesis of several human diseases, but the mechanisms regulating KIT signaling have not been fully characterized. Here, we show that stem cell factor (SCF), the ligand for KIT, induces the interaction between KIT and Cbl proteins and their mutual degradation. Upon SCF stimulation, KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. We propose a negative feedback loop controlling the SCF-KIT signaling pathway, in which SCF activates KIT. The activated KIT in turn induces phosphorylation and activation of Cbl proteins. The Cbl proteins then bind and direct the degradation of activated KIT, leading to down-regulation of KIT signaling.