Suppression of normal and malignant kit signaling by a bispecific antibody linking kit with CD300a
Suppression of normal and malignant kit signaling by a bispecific antibody linking kit with CD300a
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DOI：
10.4049/jimmunol.180.9.6064
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发表时间：
2008-05-01
影响因子：
4.4
通讯作者：
Levi-Schaffer, Francesca
中科院分区：
文献类型：
--
作者：
Bachelet, Ido;Munitz, Ariel;Levi-Schaffer, Francesca
干细胞因子(SCF)通过其受体试剂盒(CD117)对人肥大细胞(MC)的分化、存活、启动和激活起关键作用。SCF在设置这些参数方面的优势迫使严格的反调节来维持平衡的MC表型。我们已经合成了一个双特异性抗体片段文库，以检测Kit与CD300a连接的效果。在本研究中，我们报道CD300a对Kit介导的SCF诱导的信号转导有很强的抑制作用，从而在体外损害MC的分化、存活和激活。这种作用源于Kit介导的CD300a酪氨酸磷酸化和SHIP-1的募集，而不是SH2蛋白磷酸酶1的募集。CD300a抑制人白血病HMC-1细胞的结构性激活，但不能抑制其存活。最后，在皮肤过敏反应的小鼠模型中，CD300a取消了SCF引起的过敏反应。我们的发现强调了CD300a是人MC中Kit的一个新的调节因子，并提示该受体在MC相关疾病中作为Kit信号的抑制者所起的作用。
Through its receptor Kit (CD117), stem cell factor (SCF) critically regulates human mast cell (MC) differentiation, survival, priming, and activation. The dominance of SCF in setting these parameters compels stringent contra-regulation to maintain a balanced MC phenotype. We have synthesized a library of bispecific Ab fragments to examine the effect of linking Kit with CD300a. In this study, we report that CD300a exerts a strong inhibitory effect on Kit-mediated SCF-induced signaling, consequently impairing MC differentiation, survival, and activation in vitro. This effect derives from Kit-mediated tyrosine phosphorylation of CD300a and recruitment of the SHIP-1 but not of SH2-containing protein phosphatase 1. CD300a inhibits the constitutive activation of the human leukemic HMC-1 cells but not their survival. Finally, CD300a abrogates the allergic reaction induced by SCF in a murine model of cutaneous anaphylaxis. Our findings highlight CD300a as a novel regulator of Kit in human MC and suggest roles for this receptor as a suppressor of Kit signaling in MC-related disorders.