Molecular Regulation and Biological Functions of PIKE-A

PIKE-A的分子调控及其生物学功能 摘要 PIKE（PI 3-Kinase Enhancer）通过PI 3-kinase/Akt介导细胞存活 信号目前，已经表征了三种亚型：PIKE-L、-S和-A。PIKE-S是一种脑特异性 核GT3结合PI 3-激酶并刺激其脂质激酶活性。PIKE-A共扩增， CDK 4在多种人类癌症中起重要作用，最近在人类多形性胶质母细胞瘤中发现。 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。 通常，Akt在许多人类癌症中被异常激活，并在肿瘤发生中起核心作用。 然而，Akt在癌症中如何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导致更好的 了解癌症进展，但也有望提供多点治疗干预， 人类癌症最近，我们发现PIKE-A促进癌细胞侵袭并抑制细胞凋亡 通过激活Akt PIKE-A被Fyn酪氨酸激酶磷酸化，并且磷酸化是关键的 用于防止PIKE-A凋亡裂解。此外，我们表明PIKE-A是一种原癌基因， 转化NIH 3 T3细胞并刺激其侵袭。我们的初步研究表明，Akt反馈， 磷酸化PIKE-A，触发其与14-3-3的结合。然而，这一生理功能 行动仍然未知。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。作为我们长期目标的一部分，我们要了解PIKE GTdR信号级联， 细胞增殖和存活，在本申请中，我们提出：1）通过以下方法表征PIKE-A磷酸化： Akt及其与14-3-3的关联; 2）确定Akt和Fyn激酶对PIKE-A的串扰 3）研究PIKE-A在肿瘤发生中的生理功能。成功 这项研究的完成将进一步加深我们对PIKE-A在癌症生物学中的认识，并为癌症研究铺平道路。 为癌症患者确定新的药物靶点的方法。PIKE-A的分子调控及其生物学功能 项目叙述 PIKE（PI 3-Kinase Enhancer）是通过PI 3-kinase/Akt信号通路介导细胞存活的关键。 PIKE基因在多种人类癌症的12号染色体上扩增，促进癌细胞侵袭， 与具有正常PIKE拷贝数的细胞相比抑制细胞死亡。PIKE在15%的人中扩增 胶质母细胞瘤和许多其他癌症。PIKE-A特异性结合活性致癌Akt并刺激其表达。 激酶活性然而，Akt在癌症中如何调节的分子机制仍然不完全 明白人类恶性肿瘤中Akt信号级联机制的表征不仅导致了 更好地了解癌症进展，但也有望提供多点治疗， 对人类癌症的干预。最近，我们发现许多激酶磷酸化PIKE-A， 介导其与促生存效应物的关联。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。作为我们长期目标的一部分， 在细胞增殖和存活中的信号级联，在本申请中，我们提出：1）为了表征PIKE-A 通过Akt的磷酸化及其与14-3-3的关联; 2）为了确定Akt和Fyn激酶对14- 3 - 3的串扰， PIKE-A的磷酸化; 3）确定PIKE-A在肿瘤发生中的生理功能。的 这项研究有望深入了解PIKE-A在癌症生物学中的功能。完成 这些目标将导致用于治疗癌症的药物的开发。

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.