Regulation of Akt signaling activation by polyubiquitination

描述（由申请人提供）：Akt/PKB信号传导在许多生物学功能中起中心作用，例如细胞增殖、凋亡、细胞代谢和蛋白质翻译。虽然Akt的活化受磷酸化的调节是众所周知的，但还不清楚其他类型的翻译后修饰，如泛素化，是否也参与Akt的活化。在这个建议中，我们已经确定TRAF 6作为一个潜在的Akt E3连接酶，诱导Akt K63连接的多聚泛素化，是Akt磷酸化和激活的关键。我们的研究结果表明，Akt K63多聚泛素化可能代表了一种新的机制，致癌Akt信号的调节，这项研究可能有重要的临床意义的癌症治疗。本申请的目的是确定TRAF 6和Akt K63连接的多聚泛素化在癌症进展和转移中的潜在作用。本申请的中心假设是由TRAF 6诱导的Akt K63连接的多聚泛素化协调Akt膜定位和随后的磷酸化。我们的中心假设是在我们强有力的初步数据的基础上形成的。这项研究的基本原理是，一旦TRAF 6和Akt多聚泛素化在癌症进展和转移中的重要作用得到证实和确立，就可以实现对人类癌症的更好治疗或靶点。我们计划通过追求以下具体目标来测试我们的中心假设并实现本申请的目的：目的1）确定Akt多聚泛素化调节Akt活化的分子机制。目的2）探讨Akt泛素化和去泛素化的分子调控机制。目的3）研究TRAF 6在肿瘤发生和转移中的作用。这项提案工作是创新的，因为它首次提供了TRAF 6是Akt的E3连接酶，Akt K63连接的多聚泛素化协调Akt磷酸化和激活。随着受人尊敬的结果，这项提案中的工作组合有望共同揭示TRAF 6和Akt K63连接的聚泛素化在癌症发展和转移中的关键作用。这些结果将产生重要的积极影响，因为鉴定TRAF 6和Akt K63连接的多聚泛素化在癌症进展和转移中的重要作用可能因此为癌症治疗提供潜在的治疗靶点。我们的研究结果也将从根本上推进我们目前的理解致癌Akt信号是如何调节的，并可能具有重要的临床意义。

DESCRIPTION (provided by applicant): Akt/PKB signaling plays a central role in many biological functions, such as cell proliferation, apoptosis, cell metabolism, and protein translation. Although it is well known that Akt activation is regulated by phosphorylation, it is unclear whether other types of the posttranslational modifications, such as ubiquitination, are also involved in Akt activation. In this proposal, we have identified TRAF6 as a potential Akt E3 ligase that induces Akt K63-linked polyubiquitination and is critical for Akt phosphorylation and activation. Our results reveal that Akt K63 polyubiquitination may represent a novel mechanism by which oncogenic Akt signaling is regulated and that this study may have important clinical implications for the treatment of cancer. The objective of this application, which is the next step in pursuit of that goal, is to determine the potential role of TRAF6 and Akt K63-linked polyubiquitination in cancer progression and metastasis. The central hypothesis of the application is that Akt K63-linked polyubiquitination induced by TRAF6 orchestrates Akt membrane localization and subsequent phosphorylation. Our central hypothesis has been formulated on the basis of our strong preliminary data. The rationale of the proposed research is that, once the important role of TRAF6 and Akt polyubiquitination is confirmed and established in cancer progression and metastasis, the better treatment or target for human cancers can be achieved. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following specific aims: Aim 1) To determine the molecular mechanism by which Akt polyubiquitination regulates Akt activation. Aim 2) To determine the molecular mechanism by which Akt ubiquitination and deubiquitination are regulated. Aim 3) To determine in vivo role of TRAF6 in tumorigenesis and metastasis. This proposal work is innovative, because it provides for the first time that TRAF6 is an E3 ligase for Akt and Akt K63-linked polyubiquitination orchestrate Akt phosphorylation and activation. With respected outcomes, the combination of work in this proposal is collectively expected to uncover the critical role of TRAF6 and Akt K63-linked polyubiquitination in cancer development and metastasis. Such results will have an important positive impact, because identification of the important role of TRAF6 and Akt K63-linked polyubiquitination in cancer progression and metastasis may therefore provide potentially therapeutic targets for cancer treatment. Our results will also fundamentally advance our current understandings of how oncogenic Akt signaling is regulated and may have important clinical implications.