Signal Termination by PHLPP, PH domain Leucine-rich repeat Protein Phosphatase

通过 PHLPP、PH 结构域富含亮氨酸的重复蛋白磷酸酶终止信号

• 批准号: 8187235
• 负责人: ALEXANDRA C. NEWTON
• 金额: $ 30.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8187235
• 关键词: Address; Automobile Driving; Breast; Cancer Patient; Cell physiology; Cells; Disease; Functional disorder; Funding; Genetic; Glioblastoma; Goals; Growth; Growth Factor; Growth Factor Receptors; Human; Imaging technology; Life; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Messenger RNA; Modeling; Molecular; Mus; Mutation; Names; Oncogenic; PH Domain; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Prostatic Neoplasms; Protein Dephosphorylation; Protein Kinase C; Protein phosphatase; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Receptor Signaling; Regulation; Repression; Research; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Site; Testing; Tumor Suppressor Proteins; Work; cell growth; cellular imaging; inhibitor/antagonist; innovation; leucine-rich repeat protein; mouse model; neoplastic cell; novel; scaffold; small molecule; sodium-hydrogen exchanger regulatory factor; therapeutic target; tool; tumor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand the molecular, cellular and physiological mechanisms of signal termination mediated by the novel phosphatase PHLPP (PH domain Leucine- rich repeat Protein Phosphatase; pronounced 'flip') that we discovered. PHLPP terminates signaling by two oncogenic kinases, Akt and protein kinase C, by specifically dephosphorylating a key regulatory residue, the hydrophobic motif, which we originally identified on protein kinase C. PHLPP is frequently deleted in diverse human cancers and its deletion in mice promotes prostate tumors. Thus, the central hypothesis driving this proposal is that PHLPP terminates growth signaling pathways and that deregulation leads to pathophysiological states, notably cancer. Three Aims are proposed: 1. Molecular Mechanisms of PHLPP. The goals are to identify small molecule inhibitors or activators of PHLPP to use as tools in cellular studies in Aims 2 and 3. In addition, we will test the hypothesis that cancer-associated mutations in PHLPP are inactivating and thus confer a survival advantage to tumor cells. 2. Cellular Mechanisms of PHLPP. The goal of this section is to understand the mechanisms that control the function of PHLPP in cells. First, we will use innovative live cell imaging technologies to test the hypothesis that spatial coordination on the PDZ scaffold NHERF increases the ability of PHLPP to control the amplitude and duration of Akt signaling. Second, we will address the mechanism by which PHLPP suppresses the levels of growth factor receptors in cells. 3. PHLPP in pathophysiology. This Aim addresses the role of PHLPP in cancer. Specifically, we will test that hypothesis that deregulation of PHLPP by the E3 ligase 2-TrCP contributes to glioblastoma. In addition, we will address the roles of PHLPP1 and PHLPP2 in prostate cancer using a mouse model and in breast cell growth using a 3D culture model. PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it addresses the basic molecular mechanisms of cancer. Specifically, our lab discovered a new tumor suppressor that is frequently deleted in cancer and is poised as a novel and important therapeutic target. We would like to understand how to target this tumor suppressor in disease.

描述（由申请人提供）：该提案的长期目标是了解由新型磷酸酶PHLPP介导的信号终止的分子，细胞和生理机制（pH结构域 - 富含亮氨酸 - 富含重复的蛋白磷酸酶；明显的“ flip”）。 PHLPP通过特异性去磷酸化的关键调节残基（疏水基序）来终止两个致癌激酶AKT和蛋白激酶C的信号传导，我们最初在蛋白质激酶C. Phlpp上识别出疏水性基序，通常在多种人的人类癌症中及其在小鼠中的多种人类癌症中被删除。因此，推动该建议的中心假设是PHLPP终止了生长信号通路，并且放松管制导致病理生理状态，尤其是癌症。提出了三个目标：1。PHLPP的分子机制。目标是鉴定PHLPP的小分子抑制剂或活化剂在AIM 2和3中用作细胞研究的工具。此外，我们将测试以下假设：PHLPP中与癌症相关的突变灭活，从而赋予肿瘤细胞的生存优势。 2。PHLPP的细胞机制。本节的目的是了解控制细胞中PHLPP功能的机制。首先，我们将使用创新的活细胞成像技术来检验以下假设：PDZ支架上的空间协调可以提高PHLPP控制AKT信号传导幅度和持续时间的能力。其次，我们将解决PHLPP抑制细胞中生长因子受体水平的机制。 3。病理生理学中的PHLPP。这个目的解决了PHLPP在癌症中的作用。具体而言，我们将检验该假设，即E3连接酶2-TRCP对PHLPP的放松受到贡献有助于胶质母细胞瘤。此外，我们将使用小鼠模型以及使用3D培养模型来解决PHLPP1和PHLPP2在前列腺癌中的作用。 公共卫生相关性：这项研究与公共卫生有关，因为它解决了癌症的基本分子机制。具体而言，我们的实验室发现了一种新的肿瘤抑制剂，该肿瘤经常在癌症中被删除，并有望成为一种新颖而重要的治疗靶标。我们想了解如何靶向这种疾病中的肿瘤抑制剂。