Molecular Regulation and Biological Functions of PIKE-A

PIKE-A的分子调控和生物学功能

基本信息

批准号：
7849584
负责人：
KEQIANG YE
金额：
$ 32.16万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-05 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7849584
关键词：
1-Phosphatidylinositol 3-Kinase Apoptosis Apoptotic Back Binding Biological Biological Process Brain CDK4 gene Cancer Biology Cell Death Cell Proliferation Cell Survival Cells Chromosomes, Human, Pair 12 Cleaved cell Dominant-Negative Mutation Drug Delivery Systems EGF gene Enhancers Feeds Genes Glioblastoma Goals Guanosine Triphosphate Phosphohydrolases Human In Vitro Knowledge Lead Lipids Malignant Neoplasms Mediating Molecular Nuclear Oncogenic Patients Phosphorylation Phosphotransferases Physiological Play Primary Brain Neoplasms Protein Isoforms Proto-Oncogene Proteins c-fyn Proto-Oncogenes Regulation Research Resistance Role Signal Pathway Signal Transduction Testing Therapeutic Intervention Tyrosine Phosphorylation cancer cell drug development in vivo insight knock-down mutant novel overexpression prevent public health relevance research study therapy development tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): PIKE (PI 3-Kinase Enhancer) plays an essential role in mediating cell survival through PI 3-kinase/Akt signaling. Currently, three isoforms have been characterized: PIKE-L, -S and -A. PIKE-S a brain-specific nuclear GTPase, which binds to PI 3-kinase and stimulates its lipid kinase activity. PIKE-A is coamplified with CDK4 in a variety of human cancers, and it was recently identified in human glioblastoma multiformes. Interestingly, PIKE-A does not bind to PI 3-kinase, instead, it activates Akt in a GTP-dependent manner. Frequently, Akt is abnormally activated in many human cancers and plays a central role in tumorigenesis. However, the molecular mechanism how Akt is regulated in cancers remains incompletely understood. Characterization of Akt signaling cascade machinery in human malignancy not only leads to a better understanding of cancer progression but also promises to provide multiple points of therapeutic intervention for human cancers. Recently, we have showed that PIKE-A promotes cancer cell invasion and inhibits apoptosis through activating Akt. PIKE-A is phosphorylated by Fyn tyrosine kinase, and the phosphorylation is critical for preventing PIKE-A from apoptotic cleavage. Further, we show that PIKE-A is a proto-oncogene and transforms NIH3T3 cells and stimulates its invasion. Our preliminary study reveals that Akt feeds back and phosphorylates PIKE-A, triggering its association with 14-3-3. However, the physiological functions of this action remain unknown. Moreover, how the upstream Fyn and Akt kinases crosstalk mediates PIKE-A oncogenic role is unclear. We hypothesize that Akt and Fyn kinases regulate PIKE-A's pro-survival function, promoting cancer progress. As a part of our long-term goal to understand PIKE GTPase signaling cascades in cell proliferation and survival, in this application we propose: 1) To characterize PIKE-A phosphorylation by Akt and its association with 14-3-3; 2) To determine Akt and Fyn kinases crosstalk on PIKE-A phosphorylation; 3) To determine the physiological functions of PIKE-A in tumorigenesis. Successful accomplishment of the proposed study will further our knowledge about PIKE-A in cancer biology and pave the way for identification of novel drug targets for patients with cancers. PUBLIC HEALTH RELEVANCE: PIKE (PI 3-Kinase Enhancer) is critical for mediating cell survival through PI 3-kinase/Akt signaling pathway. PIKE gene is amplified on chromosome 12 in a variety of human cancers, promoting cancer cell invasion and inhibiting cell death compared to cells with normal PIKE copy number. PIKE is amplified in 15% human glioblastoma and many other cancers. PIKE-A specifically binds to active oncogenic Akt and stimulates its kinase activity. However, the molecular mechanism how Akt is regulated in cancers remains incompletely understood. Characterization of Akt signaling cascade machinery in human malignancy not only leads to a better understanding of cancer progression but also promises to provide multiple points of therapeutic intervention for human cancers. Recently, we have found that numerous kinases phosphorylate PIKE-A and mediate its association with pro-survival effectors. Thus, we hypothesize that the phosphorylation regulates PIKE-A's pro-survival function, promoting cancer progress. As a part of our long-term goal to understand PIKE signaling cascades in cell proliferation and survival, in this application we propose: 1) To characterize PIKE-A phosphorylation by Akt and its association with 14-3-3; 2) To determine Akt and Fyn kinases crosstalk on PIKE-A phosphorylation; 3) To determine the physiological functions of PIKE-A in tumorigenesis. The proposed study is expected to provide insight into the function of PIKE-A in cancer biology. Accomplishing these aims will lead to development of drugs for curing of cancers.

描述（由申请人提供）：PIKE（PI 3-激酶增强剂）通过 PI 3-激酶/Akt 信号传导在介导细胞存活中发挥重要作用。目前，已鉴定出三种亚型：PIKE-L、-S 和-A。 PIKE-S 是一种大脑特异性核 GTP 酶，可与 PI 3 激酶结合并刺激其脂质激酶活性。 PIKE-A 在多种人类癌症中与 CDK4 共扩增，最近在人类多形性胶质母细胞瘤中被发现。有趣的是，PIKE-A 不与 PI 3 激酶结合，而是以 GTP 依赖性方式激活 Akt。 Akt 通常在许多人类癌症中异常激活，并在肿瘤发生中发挥核心作用。然而，Akt 在癌症中调节的分子机制仍不完全清楚。人类恶性肿瘤中 Akt 信号级联机制的表征不仅可以更好地了解癌症进展，而且有望为人类癌症提供多点治疗干预。最近，我们发现PIKE-A通过激活Akt促进癌细胞侵袭并抑制细胞凋亡。 PIKE-A 被 Fyn 酪氨酸激酶磷酸化，磷酸化对于防止 PIKE-A 凋亡裂解至关重要。此外，我们表明 PIKE-A 是一种原癌基因，可以转化 NIH3T3 细胞并刺激其侵袭。我们的初步研究表明，Akt 反馈并磷酸化 PIKE-A，触发其与 14-3-3 的关联。然而，这种作用的生理功能仍然未知。此外，上游 Fyn 和 Akt 激酶串扰如何介导 PIKE-A 致癌作用尚不清楚。我们假设 Akt 和 Fyn 激酶调节 PIKE-A 的促生存功能，促进癌症进展。作为我们了解细胞增殖和存活中 PIKE GTPase 信号级联反应的长期目标的一部分，在本应用中，我们建议： 1) 表征 Akt 引起的 PIKE-A 磷酸化及其与 14-3-3 的关联； 2) 确定 Akt 和 Fyn 激酶对 PIKE-A 磷酸化的串扰； 3)确定PIKE-A在肿瘤发生中的生理功能。这项研究的成功完成将进一步加深我们对 PIKE-A 在癌症生物学中的了解，并为癌症患者新药物靶点的鉴定铺平道路。公共健康相关性：PIKE（PI 3 激酶增强剂）对于通过 PI 3 激酶/Akt 信号通路介导细胞存活至关重要。 PIKE基因在多种人类癌症中的12号染色体上扩增，与具有正常PIKE拷贝数的细胞相比，促进癌细胞侵袭并抑制细胞死亡。 PIKE 在 15% 的人类胶质母细胞瘤和许多其他癌症中被扩增。 PIKE-A 特异性结合活性致癌 Akt 并刺激其激酶活性。然而，Akt 在癌症中调节的分子机制仍不完全清楚。人类恶性肿瘤中 Akt 信号级联机制的表征不仅可以更好地了解癌症进展，而且有望为人类癌症提供多点治疗干预。最近，我们发现许多激酶磷酸化 PIKE-A 并介导其与促生存效应子的关联。因此，我们假设磷酸化调节 PIKE-A 的促生存功能，促进癌症进展。作为了解细胞增殖和存活中 PIKE 信号级联的长期目标的一部分，在本应用中，我们建议： 1) 表征 Akt 引起的 PIKE-A 磷酸化及其与 14-3-3 的关联； 2) 确定 Akt 和 Fyn 激酶对 PIKE-A 磷酸化的串扰； 3)确定PIKE-A在肿瘤发生中的生理功能。拟议的研究有望深入了解 PIKE-A 在癌症生物学中的功能。实现这些目标将导致治疗癌症药物的开发。