Regulation of Akt signaling activation by polyubiquitination

描述（由申请人提供）：Akt/PKB信号在许多生物学功能中起核心作用，如细胞增殖、细胞凋亡、细胞代谢和蛋白质翻译。虽然我们都知道Akt的激活是由磷酸化调控的，但目前还不清楚其他类型的翻译后修饰，如泛素化，是否也参与了Akt的激活。在本研究中，我们发现TRAF6是一种潜在的Akt E3连接酶，可诱导Akt k63连接的多泛素化，对Akt的磷酸化和激活至关重要。我们的研究结果表明，Akt K63多泛素化可能是调控致癌Akt信号的一种新机制，该研究可能对癌症的治疗具有重要的临床意义。该应用程序的目标是确定TRAF6和Akt k63相关的多泛素化在癌症进展和转移中的潜在作用，这是追求该目标的下一步。该应用的中心假设是TRAF6诱导的Akt K63-linked多泛素化调控了Akt的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制定的。本研究的基本原理是，一旦TRAF6和Akt多泛素化在癌症进展和转移中的重要作用得到证实和确立，就可以更好地治疗或靶向人类癌症。我们计划通过追求以下具体目标来验证我们的中心假设并实现本应用的目标：目的1)确定Akt多泛素化调节Akt激活的分子机制。目的2)确定Akt泛素化和去泛素化调控的分子机制。目的3)确定体内TRAF6在肿瘤发生和转移中的作用。这项研究具有创新性，因为它首次证明了TRAF6是Akt的E3连接酶，Akt k63连接的多泛素化调控了Akt的磷酸化和激活。本研究的结果令人满意，预计将共同揭示TRAF6和Akt k63相关的多泛素化在癌症发展和转移中的关键作用。这些结果将具有重要的积极影响，因为鉴定TRAF6和Akt k63相关的多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对致癌Akt信号如何调控的理解，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. PUBLIC HEALTH RELEVANCE: Although the extensive studies have been made for the role of PI3K/Akt signaling in cancers, how Akt membrane localization and phosphorylation is regulated remains largely unknown. Our study reveals that a novel posttranslational modification is operated on Akt and that Akt K63-linked polyubiquitnation by E3 ligase TRAF6 may play important roles in Akt membrane localization, phosphorylation, and tumorigenesis. Understanding the mechanism by which Akt activation is regulated may not only provide a great insight into how the oncogenic Akt signaling is regulated, but also offer the important therapeutic implications for human cancers.