THE ROLE OF NEDD4-1 IN IGF-1R SIGNALING

描述（由申请人提供）：NEDD 4 -1是一种E3泛素化连接酶，经常在人类癌症中过表达。NEDD 4 -1在肿瘤发生中起重要作用。尽管已经表明NEDD 4 -1通过促进Akt活化而作为致癌蛋白发挥功能，但NEDD 4 -1活化Akt的分子机制仍然很大程度上未知。我们发现NEDD 4 -1通过调节IGF-1 R信号通路激活Akt。引人注目的是，我们还发现NEDD 4 -1对Akt的激活受复制蛋白A（RPA）负调控，RPA是一种单链DNA（ssDNA）结合蛋白，通常认为其在DNA代谢中起关键作用。因此，我们提出了一项研究，以测试核心假设，即NEDD 4 -1通过激活IGF-1 R信号传导在细胞增殖中发挥作用，并且该途径被RPA抑制。因此，通过IGF-1 R抗体和/或RPA的IGF-1 R抑制特异性抑制过表达NEDD 4 -1的细胞的生长。提出了三个相互关联的具体目标来检验我们的假设。目的1研究NEDD 4 -1通过调节IGF-1 R信号通路在细胞增殖中的作用。目的2将描述RPA如何调节NEDD 4 -1依赖性IGF-1 R信号转导。目的3将确定在过表达NEDD 4 -1的细胞中阻断IGF-1 R信号传导的抗肿瘤活性。我们期望（1）确定NEDD 4 -1通过调节IGF-1 R信号促进细胞增殖的分子机制;（2）鉴定RPA通过与NEDD 4 -1相互作用抑制IGF-1 R信号的新功能;（3）发现通过RPA和/或IGF-1 R抗体抑制IGF-1 R可以特异性靶向过表达NEDD 4 -1的癌细胞的生长。预期的结果将从根本上推进我们对NEDD 4 -1相关癌症发展的分子机制的理解。此外，RPA在抑制IGF-1 R信号传导中的新功能的鉴定将促进靶向NEDD 4 -1或IGF-1 R的新型药物的开发。此外，预期的结果将通过识别NEDD 4 -1过表达的癌症患者，基于更好地预测肿瘤对IGR-1 R抑制的反应，改善癌症治疗计划的指导。

DESCRIPTION (provided by applicant): NEDD4-1 is an E3 ubiquitination ligase that is frequently over-expressed in human cancers. NEDD4-1 plays an important role in tumorigenesis. Although it has been suggested that NEDD4-1 functions as an oncogenic protein by facilitation of Akt activation, the molecular mechanisms by which NEDD4-1 activates Akt remain largely unknown. We found that NEDD4-1 activates Akt via regulation of IGF-1R signaling. Strikingly, we also found that activation of Akt by NEDD4-1 is negatively regulated by replication protein A (RPA), a single strand DNA (ssDNA) binding protein which is generally believed to play a critical role in DNA metabolism. Thus, we are proposing a study to test the central hypothesis that NEDD4-1 plays a role in cell proliferation via activation of IGF-1R signaling and this pathway is inhibited by RPA. Therefore, growth of cells overexpressing NEDD4-1 is specifically suppressed by IGF-1R inhibition through IGF-1R antibody and/or RPA. Three interrelated specific aims are proposed to test our hypothesis. Aim 1 will identify the role of NEDD4-1 in cell proliferation via regulation of IGF-1R signaling. Aim 2 will delineate how NEDD4-1 dependent IGF-1R signaling is regulated by RPA. Aim 3 will determine the antitumor activity of blocking IGF-1R signaling in cells over-expressing NEDD4-1. We anticipate to (1) define the molecular mechanisms by which NEDD4-1 promotes cell proliferation via regulation of IGF-1R signaling; (2) identify a novel function of RPA in suppression of IGF-1R signaling via interaction with NEDD4-1; (3) find that the growth of cancer cells over-expressing NEDD4-1 can be specifically targeted by IGF-1R inhibition through RPA and/or IGF-1R antibody. The expected results will fundamentally advance our understanding of the molecular mechanism underlying NEDD4-1 associated cancer development. In addition, identification of a novel function of RPA in suppression of IGF-1R signaling will facilitate the development of novel drugs targeting NEDD4-1 or IGF-1R. Moreover, the expected result will improve guidance for cancer treatment plans based on better predictions of tumor response to IGR-1R inhibition by identification of cancer patients with NEDD4-1 over-expression.