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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cellular Signaling and Dynamics Study Section (CSD)
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Jones, Warren
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University of Pennsylvania
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Zhou, Guo-Lei; Zhang, Haitao; Wu, Huhehasi et al. (2014) Phosphorylation of the cytoskeletal protein CAP1 controls its association with cofilin and actin. J Cell Sci 127:5052-65
Abedin, Zahidur; Louis-Juste, Melissa; Stangl, Melissa et al. (2013) The role of base excision repair genes OGG1, APN1 and APN2 in benzo[a]pyrene-7,8-dione induced p53 mutagenesis. Mutat Res 750:121-8
Licciulli, Silvia; Maksimoska, Jasna; Zhou, Chun et al. (2013) FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas. J Biol Chem 288:29105-14
Zhang, Haitao; Ghai, Pooja; Wu, Huhehasi et al. (2013) Mammalian adenylyl cyclase-associated protein 1 (CAP1) regulates cofilin function, the actin cytoskeleton, and cell adhesion. J Biol Chem 288:20966-77
Abedin, Zahidur; Sen, Sushmita; Field, Jeffrey (2012) Aldo-keto reductases protect lung adenocarcinoma cells from the acute toxicity of B[a]P-7,8-trans-dihydrodiol. Chem Res Toxicol 25:113-21
Sen, Sushmita; Bhojnagarwala, Pratik; Francey, Lauren et al. (2012) p53 Mutagenesis by benzo[a]pyrene derived radical cations. Chem Res Toxicol 25:2117-26
Ye, Diana Z; Jin, Shenghao; Zhuo, Ya et al. (2011) p21-Activated kinase 1 (Pak1) phosphorylates BAD directly at serine 111 in vitro and indirectly through Raf-1 at serine 112. PLoS One 6:e27637
Dummler, Bettina; Ohshiro, Kazufumi; Kumar, Rakesh et al. (2009) Pak protein kinases and their role in cancer. Cancer Metastasis Rev 28:51-63
Wang, Changhui; Zhou, Guo-Lei; Vedantam, Srilakshmi et al. (2008) Mitochondrial shuttling of CAP1 promotes actin- and cofilin-dependent apoptosis. J Cell Sci 121:2913-20
Park, Jong-Heum; Gelhaus, Stacy; Vedantam, Srilakshmi et al. (2008) The pattern of p53 mutations caused by PAH o-quinones is driven by 8-oxo-dGuo formation while the spectrum of mutations is determined by biological selection for dominance. Chem Res Toxicol 21:1039-49

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