Pak Protein Kinases in Transformation & Survival

Pak 蛋白激酶的转化

基本信息

批准号：
6621216
负责人：
JEFFREY M FIELD
金额：
$ 36.74万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-04-01 至 2006-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Our long-term goals are to understand how signaling pathways regulated by oncogenes interact with each other to transform cells. Ras is one of the most common proto-oncogenes found mutated in tumors. When Ras transforms cells, it alters several basic properties of the cell by modifying key transcription factors to promote cell proliferation, rearranging the actin cytoskeleton to stimulate invasion and inhibiting apoptosis to promote survival. Thus, studying the signals from oncogenes to their multiple targets may provide insights into how tumor growth is coordinated. Many effects of Ras, both proliferative and cytoskeletal, are regulated through the coordinated actions of the Rho family of G proteins, including members such as, Rac, Rho and Cdc42. However, the signals beyond these small G proteins that mediate Ras transformation remain to be elucidated. Rac and Cdc42 bind several proteins, including members of a highly conserved family of protein kinases known as Paks. The Pak kinases are candidates for downstream effectors that regulate both transcription and the cytoskeleton. Our preliminary results demonstrate, for the first time, a direct link between Pak and cell transformation. We found that Ras transformation can be inhibited by expression of specific Pak mutants. This type of mutation, usually called a dominant negative mutation, provides a powerful tool to explore the role of Pak in Ras transformation. Furthermore, we traced a signal from Ras through Pak to the downstream kinase, Erk. We also developed several assay systems showing for the first time that Ras activates Pak through a linear pathway requiring PT 3-kinase and a small G protein (Rac or Cdc42). Unexpectedly, one of the key intermediates is the Akt proto-oncogene, which transduces cell survival signals through Pak to a cell survival factor called Bad. This signal inhibits apoptosis. Together, these data demonstrated a new Ras signaling pathway and provided the first evidence for transformation signals through a specific effector of the Rho family. This proposal aims to build on our earlier work by tracing the signals step by step from Ras to Pak and linking Pak to another oncogene, Abl. We hypothesize that Pak is a convergence point for Ras and Abl to transduce signals to transformation and survival pathways. We will: (1) Determine the signals from Ras to Pak. (2) Determine the role of Pak in cell survival signals through Bad. (3) Determine the role of the RasPak module in signaling by the Abl oncogene.

描述（由申请人提供）：我们的长期目标是了解如何癌基因调控的信号通路相互作用发生转化细胞。 Ras 是肿瘤中最常见的突变原癌基因之一。当 Ras 转化细胞时，它会通过以下方式改变细胞的几个基本特性：修饰关键转录因子以促进细胞增殖、重新排列肌动蛋白细胞骨架刺激侵袭并抑制细胞凋亡促进生存。因此，研究从癌基因到其多重基因的信号目标可以提供有关肿瘤生长如何协调的见解。多种效果 Ras 的增殖和细胞骨架均通过 G 蛋白 Rho 家族的协调作用，包括以下成员： Rac、Rho 和 Cdc42。然而，这些小 G 蛋白之外的信号介导 Ras 转化仍有待阐明。 Rac 和 Cdc42 结合了几个蛋白质，包括高度保守的蛋白激酶家族的成员被称为帕克斯。 Pak 激酶是下游效应器的候选者，调节转录和细胞骨架。我们的初步结果首次证明 Pak 和细胞之间的直接联系转变。我们发现Ras转化可以被表达抑制特定的 Pak 突变体。这种类型的突变通常称为显性突变负突变，为探索 Pak 在 Ras 中的作用提供了有力的工具转变。此外，我们追踪了从 Ras 到 Pak 的信号下游激酶，Erk。我们还开发了几种检测系统，显示 Ras 第一次通过需要 PT 的线性途径激活 Pak 3-激酶和一个小 G 蛋白（Rac 或 Cdc42）。没想到关键之一中间体是 Akt 原癌基因，可转导细胞生存信号通过 Pak 转化为一种称为 Bad 的细胞生存因子。该信号抑制细胞凋亡。这些数据共同证明了一种新的 Ras 信号通路通过特定的方法提供了转化信号的第一个证据 Rho家族的效应者。该提案旨在以我们早期工作为基础逐步追踪从 Ras 到 Pak 的信号，并将 Pak 连接到另一个癌基因，Abl。我们假设 Pak 是 Ras 和 Abl 的汇聚点将信号转导至转化和生存途径。我们将：（1）确定从 Ras 到 Pak 的信号。 (2)确定Pak在细胞中的作用通过“坏”发出生存信号。 (3)确定RasPak模块的作用 Abl 癌基因的信号传导。