Pak Protein Kinases in Transformation & Survival

描述（由申请人提供）：我们的长期目标是了解如何 由癌基因调控的信号通路相互作用， 细胞Ras是肿瘤中最常见的原癌基因突变之一。 当Ras转换细胞时，它会改变细胞的几个基本属性， 修饰关键转录因子以促进细胞增殖，重排 肌动蛋白细胞骨架刺激侵袭和抑制凋亡， 促进生存。因此，研究从癌基因到其多重癌基因的信号 靶点可以提供关于肿瘤生长如何协调的见解。许多影响 Ras的增殖和细胞骨架，都是通过 G蛋白的Rho家族的协调作用，包括诸如， Rac、Rho和Cdc42。然而，这些小G蛋白以外的信号， 介导的Ras转化仍有待阐明。Rac和Cdc42结合几种 蛋白质，包括高度保守的蛋白激酶家族成员 被称为Paks。Pak激酶是下游效应子的候选者， 调节转录和细胞骨架。我们的初步结果 第一次展示了巴基斯坦和细胞之间的直接联系， 转型我们发现Ras转化可以被表达抑制 特定的Pak突变体这种类型的突变，通常被称为显性突变， 负突变，为探讨Pak在Ras中的作用提供了有力的工具 转型此外，我们追踪了一个从Ras到Pak的信号 下游激酶，Erk。我们还开发了几种检测系统， Ras首次通过需要PT的线性途径激活Pak 3-激酶和小G蛋白（Rac或Cdc42）。出乎意料的是， 中间体是Akt原癌基因，其转导细胞存活信号 通过Pak转化为细胞存活因子Bad这个信号抑制了 凋亡总之，这些数据证明了一种新的Ras信号通路， 提供了第一个证据，通过特定的转换信号， Rho家族的效应子这项建议旨在以我们先前的工作为基础， 逐步追踪从Ras到Pak的信号，并将Pak与另一个连接起来 我们假设Pak是Ras和Abl的会聚点， 来传递转化和生存途径的信号。我们将：（1） 确定从Ras到Pak的信号。(2)确定Pak在细胞中的作用 生存信号通过坏。(3)确定RasPak模块在 Abl癌基因的信号传导。

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.