The Role of CbL in AbL Signaling and Leukemia

描述（由申请人提供）：原癌蛋白c-Abl的过度活化可能导致各种形式的白血病。有证据表明，c-Abl的活性可通过泛素依赖性降解而下调，但其分子机制尚不清楚。Cbl蛋白家族是E3泛素连接酶。它们被c-Abl磷酸化，并在c-Abl活化后与c-Abl和c-Abl下游的其他信号分子（如CrkL、PI-3激酶的p85和Vav）缔合。由于Cbl蛋白促进相关分子的泛素化，因此这些分子与Cbl蛋白之间的相互作用可能在各种细胞功能和细胞转化所需的c-Abl信号传导中具有重要作用。 我们的假设是Cbl蛋白在两个水平上负调节c-Abl信号：1）通过促进活化的c-Abl的泛素化和降解，2）通过促进c-Abl下游信号分子如CrkL、p85 PI-3 K和Vav的泛素化。这种调节的丧失可能导致Abl信号传导的过度激活，以及可能的细胞过度增殖和恶性转化。为了研究这一假设，我们已经产生了几个突变株的小鼠c-Cbl或Cbl-b单独或同时在特定的组织，以及小鼠表达的突变Cbl缺乏泛素连接酶活性，但仍然保留了多接头功能。在这里，我们建议调查： 1)Cbl蛋白在c-Abl信号转导中的作用及其调控机制 2)c-Abl和Cbl蛋白相互作用在白血病发生发展中的意义 这项研究的完成将提供深入了解Cbl蛋白在Abl信号传导和cb诱导的白血病中的调节作用。为今后白血病的预防和临床治疗提供了新的手段。

DESCRIPTION (provided by applicant): Hyper-activation of proto-oncoprotein c-Abl may cause various forms of leukemia. Evidence suggests that the activity of c-Abl can be downregulated by ubiquitin-dependent degradation of c-Abl. However, molecular mechanisms underlying this process is not clear. The Cbl family of proteins are E3 ubiquitin ligases. They are phosphorylated by c-Abl and associate with c-Abl and other signaling molecules downstream of c-Abl, such as CrkL, p85 of PI-3 kinase and Vav, upon c-Abl activation. Since Cbl proteins promote ubiquitination of the associated molecules, the interplay between these molecules and Cbl proteins may have a significant role in c-Abl signaling required for various cellular functions and cell transformation. Our hypothesis is that Cbl proteins negatively regulate c-Abl signaling at two levels: 1) by promoting ubquitination and degradation of the activated c-Abl. 2) by facilitating ubiquitination of c-Abl downstream signaling molecules, such as CrkL, p85PI-3K and Vav. Loss of such regulations may lead to hyperactivation of Abl signaling, and possibly hyperproliferation and malignant transformation of cell. To study this hypothesis, we have generated several mutant strains of mice deficient in either c-Cbl or Cbl-b alone or simultaneously in specific tissues, as well as mice expressing a mutant Cbl that lacks the ubiqutin ligase activity but still retains the multi-adaptor function. Here, we propose to investigate: 1) The role and regulatory mechanisms of Cbl proteins in c-Abl signaling. 2) The significance of interplay between c-Abl and Cbl proteins in the development of leukemia. Completion of this study will provide insight into the regulatory role of Cbl proteins in Abl signaling and Abl-induced leukemia. It may also provide tools for future prevention and clinic therapy of leukemia.