The Role of CbL in AbL Signaling and Leukemia

描述(申请人提供)：原癌蛋白c-Abl的过度激活可能导致各种形式的白血病。有证据表明，c-Abl的活性可被泛素依赖的c-Abl降解下调。然而，这一过程背后的分子机制尚不清楚。Cbl家族蛋白是E3泛素连接酶。它们被c-Abl磷酸化，并在c-Abl激活后与c-Abl及c-Abl下游的其他信号分子如CrkL、PI-3激酶的P85和Vav结合。由于Cbl蛋白促进相关分子的泛素化，这些分子与Cbl蛋白之间的相互作用可能在多种细胞功能和细胞转化所需的c-Abl信号转导中发挥重要作用。 我们的假设是，Cbl蛋白在两个水平上负向调节c-Abl信号：1)促进激活的c-Abl的泛素化和降解。2)通过促进c-Abl下游信号分子的泛素化，如CrkL、p85PI-3K和Vav。这些调控的缺失可能导致Abl信号的过度激活，并可能导致细胞的过度增殖和恶性转化。为了研究这一假设，我们产生了几个突变株的小鼠，在特定组织中单独或同时缺乏c-Cbl或Cbl-b，以及表达缺乏泛素连接酶活性但仍保留多接头功能的突变Cbl的小鼠。在此，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。这项研究的完成将有助于深入了解Cbl蛋白在Abl信号转导和Abl诱导的白血病中的调节作用。它还可能为未来白血病的预防和临床治疗提供工具。

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.