Functions of EPH Receptors and Ephrins in Neuroblastoma

EPH 受体和 Ephrins 在神经母细胞瘤中的功能

• 批准号: 6514413
• 负责人: NAOHIKO IKEGAKI
• 金额: $ 31.97万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514413
• 关键词: DNA methylation; amidohydrolases; angiogenesis; athymic mouse; cell growth regulation; enzyme activity; growth factor receptors; insulinlike growth factor; membrane proteins; metastasis; neoplasm /cancer genetics; neuroblastoma; pediatric neoplasm /cancer; protein structure function; protein tyrosine kinase

DESCRIPTION: (provided by applicant) EPH family receptor protein-tyrosine kinases and ephrin ligands play important roles in neural and cardiovasular development. Our recent study has shown that high-level expression of EPHB6, ephrin-B2, and ephrin-B3 predicts favorable disease outcome of neuroblastoma (NB), a common pediatric tumor of neural crest origin. The goal of this study is to elucidate the underlying mechanisms by which EPHB6, ephrin-B2, and ephrin-B3 provide NB cells with favorable phenotype. EPHIB6 lacks its kinase activity due to a mutation at the ATP acceptor site. Ephrin-B ligands are bi-functional molecules in that their extracellular domains promote angiogenesis and their cytoplasmic domains suppress the growth-promoting activity of activated protein-tyrosine kinases. Based on these observations, we hypothesize that EPHB6 restricts growth, angiogenesis and metastasis of NB cells by acting as a dominant negative member among the EPHB receptor family and/or by sequestering ephrin-B ligands from participating in angiogenesis. Cytoplasmic domains of ephrin-B ligands may inhibit NB growth by suppressing the growth stimulatory effect of receptor tyrosine kinases (IGF1R and TrkA) that are highly expressed by favorable NB. To test these hypotheses, we will examine whether EPHB6 restricts growth, angiogenesis and metastasis of NB cells. We will also examine whether extracellular domains of ephrin-B2 and ephrin-B3, in the absence of EPHB6, facilitate angiogenesis and metastasis of NB and whether EPHB6 blocks the action of ephrin-B ligands in facilitating these processes. We will investigate whether cytoplasmic domains of ephrin-B2 and ephrin-B3 suppress the growth promoting activity of IGF1R and TrkA. Lastly, we will examine whether inhibitors of DNA methylation and histone deacetylation increase EPHB6, ephrin-B2, and ephrin-B3 expressions in unfavorable NB cells, and if so, how these changes affect growth, angiogenesis and metastasis of unfavorable NB cells. Results of this study would reveal novel mechanisms by which EPHB6 and ephrin-B ligands restrict growth, angiogenesis and metastasis of NB. Such knowledge may help develop an innovative and effective treatment for unfavorable NB.

描述：（由申请人提供）EPH家族受体蛋白 - 酪氨酸 激酶和ephrin配体在神经和心脏中起重要作用 发展。我们最近的研究表明，EPHB6的高级表达， Ephrin-B2和Ephrin-B3预测神经母细胞瘤的有利疾病结果 （NB），一种神经rest的常见小儿肿瘤。这项研究的目标 是为了阐明ephb6，ephrin-b2和 ephrin-b3为NB细胞提供了有利的表型。埃菲布6缺乏激酶 由于ATP受体部位突变而导致的活动。 ephrin-b配体是 双功能分子的细胞外域促进 血管生成及其细胞质结构域抑制了生长促进 活化的蛋白质酪氨酸激酶的活性。基于这些观察，我们 假设EPHB6限制了NB的生长，血管生成和转移 通过充当EPHB受体家族中的主要负成员的细胞 和/或通过参与血管生成而隔离ephrin-b配体。 ephrin-b配体的细胞质结构域可能通过抑制抑制NB的生长 受体酪氨酸激酶（IGF1R和TRKA）的生长刺激作用 由有利的NB高度表达。为了检验这些假设，我们将 检查EPHB6是否限制了NB的生长，血管生成和转移 细胞。我们还将检查ephrin-B2和 在没有EPHB6的情况下，ephrin-b3促进了血管生成和转移 NB以及EPHB6是否阻止了Ephrin-B配体的作用 这些过程。我们将研究ephrin-b2的细胞质结构域 Ephrin-B3抑制了IGF1R和TRKA的生长活性。最后， 我们将检查DNA甲基化和组蛋白脱乙酰化的抑制剂是否存在 在不利的NB细胞中增加Ephb6，Ephrin-B2和Ephrin-B3表达式， 如果是这样，这些变化如何影响生长，血管生成和转移 不利的NB细胞。这项研究的结果将通过 ephb6和ephrin-b配体限制了生长，血管生成和转移 NB。这种知识可能有助于开发创新有效的治疗 对于不利的NB。