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：
8266876
负责人：
KEQIANG YE
金额：
$ 31.2万
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 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8266876
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 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 abstracting cancer cell drug development in vivo insight knock-down mutant novel overexpression prevent research study therapy development tumor progression tumorigenesis tumorigenic

项目摘要

Molecular Regulation and Biological Functions of PIKE-A Abstract 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. Molecular Regulation and Biological Functions of PIKE-A Project Narrative 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.

派克A的分子调节和生物学功能抽象的派克（PI 3-激酶增强剂）在通过PI 3-激酶/AKT中介导细胞存活中起着至关重要的作用信号。目前，已经表征了三种同工型：派克-L，-s和-a。派克-S特定于大脑核GTPase与PI 3-激酶结合并刺激其脂质激酶活性。 Pike-A与各种人类癌症中的CDK4，最近在人类胶质母细胞瘤多形中鉴定出来。有趣的是，派克A不与PI 3-激酶结合，而是以GTP依赖性方式激活AKT。通常，AKT在许多人类癌症中被异常激活，并且在肿瘤发生中起着核心作用。但是，在癌症中调节AKT的分子机制仍然不完全理解。 AKT信号传导级联机械的表征人类恶性肿瘤不仅会导致更好了解癌症进展，但也有望提供多种治疗干预措施人类癌。最近，我们表明派克A促进癌细胞侵袭并抑制凋亡通过激活AKT。派克-A被FYN酪氨酸激酶磷酸化，并且磷酸化至关重要用于防止派克A的凋亡裂解。此外，我们表明派克A是一种原始癌基因，转化NIH3T3细胞并刺激其侵袭。我们的初步研究表明，Akt馈回并磷酸化派克-a，触发其与14-3-3的关联。但是，这是生理功能动作仍然未知。此外，上游Fyn和Akt激酶如何介导Pike-a 致癌作用尚不清楚。我们假设Akt和Fyn激酶调节了派克-A的亲寿使功能，促进癌症进展。作为我们的长期目标的一部分，了解派克GTPase信号级联细胞增殖和生存，在此应用中，我们提出：1）表征派克A磷酸化。 AKT及其与14-3-3的关联； 2）确定派克A上的Akt和Fyn激酶串扰磷酸化； 3）确定派克A在肿瘤发生中的生理功能。成功的拟议的研究的完成将进一步我们对癌症生物学中的派克A的了解，并铺平鉴定癌症患者的新药物靶标。派克A的分子调节和生物学功能项目叙述派克（PI 3-激酶增强子）对于通过PI 3-激酶/AKT信号通路介导细胞存活至关重要。派克基因在多种人类癌症中的12染色体上被扩增，从而促进癌细胞侵袭和与正常派克拷贝数的细胞相比，抑制细胞死亡。派克在15％的人类中被放大胶质母细胞瘤和许多其他癌症。派克A特异性结合了主动的致癌Akt并刺激其激酶活性。但是，分子机制在癌症中如何调节Akt的机制仍然不完全理解。 Akt信号传导级联机械在人类恶性肿瘤中的表征不仅导致更好地了解癌症的进展，但也有望提供多种治疗点干预人类癌症。最近，我们发现许多激酶磷酸化派克-a和调解其与促生物效应子的关联。因此，我们假设磷酸化调节 Pike-A的亲寿使功能，促进癌症的进展。作为我们理解派克的长期目标的一部分在细胞增殖和存活中发出信号级联 AKT及其与14-3-3的关联磷酸化； 2）确定Akt和Fyn激酶在派克-A磷酸化； 3）确定派克A在肿瘤发生中的生理功能。这预计拟议的研究将洞悉派克A在癌症生物学中的功能。完成这些目标将导致开发用于治愈癌症的药物。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of a small molecular insulin receptor agonist with potent antidiabetes activity.

DOI：
10.2337/db13-0334
发表时间：
2014-04
期刊：
Diabetes
影响因子：
7.7
作者：
Qiang G;Xue S;Yang JJ;Du G;Pang X;Li X;Goswami D;Griffin PR;Ortlund EA;Chan CB;Ye K
通讯作者：
Ye K

Acridine yellow G blocks glioblastoma growth via dual inhibition of epidermal growth factor receptor and protein kinase C kinases.

吖啶黄 G 通过表皮生长因子受体和蛋白激酶 C 激酶的双重抑制来阻断胶质母细胞瘤的生长。

DOI：
10.1074/jbc.m111.293605
发表时间：
2012
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Qi,Qi;He,Kunyan;Yoo,Min-Heui;Chan,Chi-Bun;Liu,Xia;Zhang,Zhaobin;Olson,JeffreyJ;Xiao,Ge;Wang,Liya;Mao,Hui;Fu,Haian;Tao,Hui;Ramalingam,SureshS;Sun,Shi-Yong;Mischel,PaulS;Ye,Keqiang
通讯作者：
Ye,Keqiang

Deoxygedunin, a natural product with potent neurotrophic activity in mice.

DOI：
10.1371/journal.pone.0011528
发表时间：
2010-07-13
期刊：
PloS one
影响因子：
3.7
作者：
Jang SW;Liu X;Chan CB;France SA;Sayeed I;Tang W;Lin X;Xiao G;Andero R;Chang Q;Ressler KJ;Ye K
通讯作者：
Ye K

The roles of PIKE in tumorigenesis.