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首页> 外文期刊>Molecular and Cellular Biology >Tissue Hyperplasia and Enhanced T-Cell Signalling via ZAP-70 in c-Cbl-Deficient Mice
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Tissue Hyperplasia and Enhanced T-Cell Signalling via ZAP-70 in c-Cbl-Deficient Mice

机译：c-Cbl缺陷小鼠中通过ZAP-70的组织增生和增强的T细胞信号传导

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The c-Cbl protein is tyrosine phosphorylated and forms complexes with a wide range of signalling partners in response to various growth factors. How c-Cbl interacts with proteins, such as Grb2, phosphatidylinositol 3-kinase, and phosphorylated receptors, is well understood, but its role in these complexes is unclear. Recently, theCaenorhabditis elegans Cbl homolog, Sli-1, was shown to act as a negative regulator of epidermal growth factor receptor signalling. This finding forced a reassessment of the role of Cbl proteins and highlighted the desirability of testing genetically whether c-Cbl acts as a negative regulator of mammalian signalling. Here we investigate the role of c-Cbl in development and homeostasis in mice by targeted disruption of the c-Cbl locus. c-Cbl-deficient mice were viable, fertile, and outwardly normal in appearance. Bone development and remodelling also appeared normal in c-Cbl mutants, despite a previously reported requirement for c-Cbl in osteoclast function. However, consistent with a high level of expression of c-Cbl in the hemopoietic compartment, c-Cbl-deficient mice displayed marked changes in their hemopoietic profiles, including altered T-cell receptor expression, lymphoid hyperplasia, and primary splenic extramedullary hemopoiesis. The mammary fat pads of mutant female mice also showed increased ductal density and branching compared to those of their wild-type littermates, indicating an unanticipated role for c-Cbl in regulating mammary growth. Collectively, the hyperplastic histological changes seen in c-Cbl mutant mice are indicative of a normal role for c-Cbl in negatively regulating signalling events that control cell growth. Consistent with this view, we observed greatly increased intracellular protein tyrosine phosphorylation in thymocytes following CD3ε cross-linking. In particular, phosphorylation of ZAP-70 kinase in thymocytes was uncoupled from a requirement for CD4-mediated Lck activation. This study provides the first biochemical characterization of any organism that is deficient in a member of this unique protein family. Our findings demonstrate critical roles for c-Cbl in hemopoiesis and in controlling cellular proliferation and signalling by the Syk/ZAP-70 family of protein kinases.
机译：c-Cbl蛋白被酪氨酸磷酸化，并响应各种生长因子而与多种信号分子形成复合物。 c-Cbl如何与蛋白质相互作用，例如Grb2，磷脂酰肌醇3-激酶和磷酸化受体，这一点已广为人知，但尚不清楚其在这些复合物中的作用。最近，显示了秀丽隐杆线虫Cbl同源物Sli-1充当表皮生长因子受体信号转导的负调节剂。这一发现迫使人们重新评估了Cbl蛋白的作用，并突出了对基因进行c-Cbl蛋白是否能作为哺乳动物信号转导负调节剂进行测试的必要性。在这里，我们通过有针对性地破坏c- Cbl 基因座来研究c-Cbl在小鼠发育和体内稳态中的作用。缺乏c-Cbl的小鼠在外观上是可行的，可育的并且向外正常。尽管先前报道了破骨细胞功能中对c-Cbl的要求，但c-Cbl突变体的骨发育和重塑也很正常。但是，与造血区室中c-Cbl的高水平表达相一致，c-Cbl缺陷型小鼠的造血特征发生了显着变化，包括T细胞受体表达改变，淋巴样增生和原发性脾髓外造血。与野生型同窝小鼠相比，突变雌性小鼠的乳腺脂肪垫还显示出增加的导管密度和分支，这表明c-Cbl在调节乳腺生长中具有意想不到的作用。总的来说，在c-Cbl突变小鼠中观察到的增生组织学变化指示c-Cbl在负调节控制细胞生长的信号事件中的正常作用。与此观点一致，我们观察到CD3ε交联后胸腺细胞中细胞内蛋白质酪氨酸磷酸化大大增加。特别是，胸腺细胞中ZAP-70激酶的磷酸化与CD4介导的Lck激活的要求是不相关的。这项研究提供了对该独特蛋白质家族成员中不足的任何生物的首次生化鉴定。我们的发现证明c-Cbl在造血中以及在控制细胞增殖和Syk / ZAP-70蛋白激酶家族信号传导中的关键作用。

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