Role of Pak kinases in survival and motility

描述（由申请人提供）：肿瘤细胞与正常细胞的区别在于不受控制的增殖、侵袭其他组织和抗凋亡。我们的长期目标是了解癌基因（尤其是Ras）如何促进这些特性。Ras结合和激活的主要效应子是Raf蛋白激酶，但关键的转化信号是通过直接结合其他效应子介导的，包括磷脂酰肌醇-3-OH激酶（PI 3-激酶）。PI 3-激酶向Akt发出信号以抑制细胞凋亡，并向小GTP酶如Rac发出信号以促进细胞侵袭。Rac调节一种名为Pak的丝氨酸苏氨酸蛋白激酶。我们的研究提供了Pak介导Ras细胞转化信号的第一个证据。除了其对Ras转化的要求之外，我们发现Pak通过磷酸化Raf-1并使其易位至线粒体、结合Bcl-2并磷酸化细胞存活因子BAD来刺激细胞存活。Pak还通过其对肌动蛋白细胞骨架的影响来调节细胞运动。我们一直在研究Akt在细胞迁移中的作用，并将Pak与此过程联系起来。有趣的是，Akt 1和Akt 2亚型在细胞迁移和Pak调节中具有相反的作用。我们发现Akt 1促进细胞运动和迁移，而Akt 2抑制细胞迁移和Pak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对细胞存活影响的潜在机制（2）确定Akt 1和Akt 2对Pak和细胞运动性的不同影响的机制（3）确定Pak和Akt在恶性外周神经鞘瘤（MPNST）及其起源的许旺细胞的迁移和存活中的作用：与公众健康的相关性-癌细胞与正常细胞的几个区别，包括侵入周围组织的能力和对程序性细胞死亡的抵抗力。这项资助计划研究一些控制细胞死亡和入侵的基因，长期目标是了解如何利用这些知识来设计更好的癌症疗法。

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.