The cytoskeleton in cell signaling and cancer
Mutations in a group of genes called oncogenes lead to the uncontrolled growth that is the hallmark of cancer. Oncogenes express proteins that regulate signaling pathways essential to the tumor cell. Identifying these pathways will ultimately lead to the best targets for pharmacological intervention. We study the Ras oncogene, one of the most commonly mutated oncogenes as well as one of the most highly conserved signaling proteins. Mutational activation of Ras causes changes in three basic properties of cells. These are: (1) increases in cell proliferation to stimulate growth, (2) reorganization of the actin cytoskeleton to promote invasion and metastases and (3) inhibition of apoptosis to prevent tumor cells from undergoing programmed cell death. We have traced a new Ras signaling pathway to a protein kinase called Pak. Our approach has been to integrate biochemical studies of the signals from Ras to Pak with cell culture studies to determine the role of Pak in Ras biology. Perhaps most striking is our observation that inhibition of Pak in cells with a technique known as dominant negatives reverted tumor cells. Ongoing studies are designed to pinpoint the steps from Ras through Pak and to determine the significance of the different steps in the biology tumor cells. For example we have found that Pak interacts with the classic ERK signaling pathway to promote proliferation and with Akt, another kinase, Akt to inhibit apoptosis. Together these studies provided the first proof-of-principle that Pak kinases are targets for new targeted therapies. Indeed, numerous companies and academic groups are developing small molecule inhibitors of Pak.
Another approach in the lab towards studying the role of the cytoskeleton in cell signaling centers on a family of proteins known as cyclase associated proteins (CAP). We discovered CAPs because they are integral to Ras signaling in yeast. They are additionally, part of a pathway that links Ras to the cytoskeleton. In mammalian cells, they are overexpressed in a number of cancers including liver and pancreatic cancer where they promote cell invasion. We recently found that CAPs signal to the mitochondrial apoptotic signaling system through a pathway that is also conserved in yeast.
Chemical carcinogenesis and lung cancer
A recent area of interest in the lab has been to develop models for lung cancer mutagenesis. Polycyclic aromatic hydrocarbons (PAH) are among the most potent carcinogens in cigarette smoke. The p53 tumor suppressor carries a unique mutagenic signature in different cancers and we have devised systems to test how PAH generate reactive oxygen to cause the signature seen in lung cancers. This pathway links one of the most potent carcinogens in tobacco with the most widely reported stress in smokers—oxidative stress.
Dr. Field directs two graduate courses (Pharm 623 and CAMB 632), directs the TREES summer program for High School students and the STEER summer program for college students.
Zhou, G. L., Zhang, H., Wu, H., Ghai, P., Field, J.: Phosphorylation of the cytoskeletal protein CAP1 controls its association with cofilin and actin. J Cell Sci in press 2014.
Licciulli, S., Maksimoska, J., Zhou, C., Troutman, S., Kota, S., Liu, Q., Duron, S., Campbell, D., Chernoff, J., Field, J., Marmorstein, R., Kissil, J. L.: FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of NF2-associated schwannomas. J Biol Chem 288: 29105-29114, 2013.
Zhang, Haitao, Ghai, Pooja, Wu, Huhehasi, Wang, Changhui, Field, Jeffrey, Zhou, Guo-Lei: Mammalian Adenylyl Cyclase-associated Protein 1 (CAP1) Regulates Cofilin Function, the Actin Cytoskeleton, and Cell Adhesion. Journal of Biological Chemistry 288(29): 20966-20977, 2013.
Abedin, Z., Sen, S., Field, J.: Aldo-Keto Reductases Protect Lung Adenocarcinoma Cells from the Acute Toxicity of B[a]P-7,8-trans-Dihydrodiol. Chem Res Toxicol 25(1): 113-21, 2012.
Ye, Diana Zi, Field, Jeffrey: PAK signaling in cancer. Cellular Logistics. Landes Bioscience Inc. 2(2): 105-116, 2012.
Sen, Sushmita, Bhojnagarwala, Pratik, Francey, Lauren, Lu, Ding, Penning, Trevor M., Field, Jeffrey: p53 Mutagenesis by Benzo[a]pyrene Derived Radical Cations. Chemical Research in Toxicology. American Chemical Society, 25(10): 2117-2126, 2012.
Wang C, Zhou G-L, Vedantam S, Li P, Field J: Mitochondrial shuttling of CAP1 promotes actin- and cofilin-dependent apoptosis. J Cell Sci 121: 2913-2920, 2008.
Ye, Diana Z., Jin, Shenghao, Zhuo, Ya, Field, Jeffrey: p21-Activated Kinase 1 (Pak1) Phosphorylates BAD Directly at Serine 111 PLoS One. Public Library of Science, 6(11): e27637, 2011.
Williams J, Su HS, Bernards A, Field J, Sehgal A: A circadian output in Drosophila mediated by neurofibromatosis-1 and Ras/MAPK. Science 293: 2251-2256, 2001.
Tang Y, Marwaha S, Rutkowski JL, Tennekoon GI, Phillips PC, Field J: A role for Pak protein kinases in Schwann cell transformation. Proc Natl Acad Sci USA 95: 5139-5144, 1998.
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Last updated: 11/05/2014
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