Role of Pak kinases in survival and motility

描述(申请人提供)：肿瘤细胞区别于正常细胞的特征包括不受控制的增殖、对其他组织的侵袭和抗凋亡。我们的长期目标是了解癌基因，特别是RAS是如何促进这些特性的。RAS结合和激活的主要效应器是Raf蛋白激酶，但关键的转换信号是通过直接与包括磷脂酰肌醇-3-羟基激酶(PI 3-Kinase)在内的其他效应器的结合来介导的。PI-3-K信号转导Akt抑制细胞凋亡，并转导Rac等小GTP酶促进细胞侵袭。Rac调节一种名为Pak的丝氨酸苏氨酸蛋白激酶。我们的研究首次提供了Pak介导RAS细胞转化信号的证据。除了对RAS转化的要求外，我们还发现Pak通过磷酸化Raf-1并使其移位到线粒体，结合Bcl2和磷酸化细胞生存因子BAD来刺激细胞存活。Pak还通过对肌动蛋白细胞骨架的影响来调节细胞的运动。我们一直在研究Akt在细胞迁移中的作用，并发现Pak参与了这一过程。有趣的是，Akt1和Akt2亚型在细胞迁移和调节PAK中具有相反的作用。我们发现Akt1促进细胞的运动和迁移，而Akt2抑制细胞的迁移和Pak的激活。我们推测，Pak通过与Raf-1和Akt的相互作用在生存和运动中发挥核心作用。我们建议(1)确定Pak影响细胞存活的潜在机制(2)确定Akt1和Akt2对Pak和细胞运动的不同影响的机制(3)确定Pak和Akt在恶性外周神经鞘瘤(MPNST)及其来源的Schwann细胞迁移和生存中的作用：与公共健康相关--癌细胞与正常细胞的几个特性，包括侵袭周围组织的能力和对细胞程序性死亡的抵抗。这笔拨款建议研究一些控制细胞死亡和侵袭的基因，长期目标是了解这些知识如何用于设计更好的癌症治疗方法。

DESCRIPTION (provided by applicant): Among the properties that distinguish tumor cells from normal cells are uncontrolled proliferation, invasion of other tissues, and resistance to apoptosis. Our long term goals are to understand how oncogenes, especially Ras, promote these properties. The major effector that Ras binds and activates is the Raf protein kinase, but critical transformation signals are mediated by direct binding to other effectors including phosphatidylinositol-3-OH kinase (PI 3-kinase). PI 3-kinase signals to Akt to inhibit apoptosis and to small GTPases such as Rac to promote cell invasion. Rac regulates a serine threonine protein kinase called Pak. Our studies provided the first evidence that Pak mediates cell transformation signals from Ras. In addition to its requirement for Ras transformation, we found that Pak stimulates cell survival by phosphorylating Raf-1 and causing it to translocate to mitochondria, bind Bcl-2 and phosphorylate the cell survival factor BAD. Pak also regulates cell motility through its effects on the actin cytoskeleton. We have been studying the role of Akt in cell migration and have implicated Pak in the process. Interestingly, the Akt1 and Akt2 isoforms have opposing roles in cell migration and regulation of Pak. We have found that Akt1 promotes motility and cell migration, while Akt2 inhibits cell migration and Pak activation. We hypothesize that Pak has central roles in survival and motility through its interactions with Raf-1 and Akt. We propose to (1) Identify the mechanisms underlying the effects of Pak on cell survival (2) Determine the mechanism responsible for the distinct effects of Akt1 and Akt2 on Pak and cell motility (3) Determine the roles of Pak and Akt in migration and survival of malignant Peripheral Nerve Sheath Tumors (MPNST) and the Schwann cells from which they originate: Relevance to public health-Several properties distinguish cancer cells from normal cells, including the ability to invade surrounding tissues and resistance to programmed cell death. This grant proposes to study some of the genes that control cell death and invasion with the long term goal of understanding how the knowledge could be used to design better cancer therapies.