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Member Information
Jeffrey Field, PhD
Associate Professor, Department of Pharmacology
Office Phone: 215-898-1912
Office Fax: 215-573-2236
Email: field@pharm.med.upenn.edu
Website(s):
Education: PhD 1985, Albert Einstein College of Medicine - Molecular Biology
Keywords: oncogenes, actin cytoskeleton, Saccharomyces cerevisiae
Research and/or Clinical Interests:
Ras signaling, focusing on the key role played by proteins that interact with the actin cytoskeleton.
Summary:
Mutations in a group of genes called oncogenes lead to the uncontrolled growth that is the hallmark of cancer. Oncogenes also rearrange the actin cytoskeleton causing dramatic changes in cell shape and invasiveness. We have taken two approaches to study the interplay between oncogenes and the actin cytoskeleton. Both center on signals through the Ras oncogene, one of the most commonly mutated oncogenes as well as one of the most highly conserved oncogenes.
The first approach exploits the Ras signaling system in the yeast Saccharomyces cerevisiae. Yeast RAS is 90% homologous to human ras and remarkably, the yeast and human homologs are functionally interchangeable. In S. cerevisiae RAS is the G-protein that activates adenylyl cyclase, the enzyme that converts ATP to the second messenger cAMP while in mammals Ras has multiple targets leading to regulation of cell growth and the actin cytoskeleton.
Purified adenylyl cyclase from yeast consists of at least two subunits, a 200 kDa catalytic subunit and a 70 kDa cyclase associated protein, CAP. We have shown that CAP is bifunctional, firstly serving as a positive regulator of cAMP levels and secondly regulating the actin cytoskeleton. CAP itself is apparently regulated by interactions with SH3 proteins. CAP is also found in mammals and its actin and SH3 binding sites are conserved. We are exploring how RAS, CAP, adenylyl cyclase and actin interact through biochemical, genetic and molecular biological studies in both the mammalian and yeast systems.
Our second approach to studying Ras and the actin cytoskeleton centers on three other small G proteins, Rho , Rac and Cdc42 which mediate the cross-talk between Ras and the actin cytoskeleton. We have determined that a Rac activated protein kinase, Pak, plays a key role in Ras transformation and may eventually be a drug target for Ras sensitive tumors.
These studies will enhance our understanding of Ras signaling, focusing on the key role played by proteins that interact with the actin cytoskeleton.
Representative Publications:
Mintzer, K., and Field, J. Interactions between adenylyl cyclase CAP and RAS from Saccharomyces Cerevisiae. Cellular Signalling, 6: 681-694, 1994.
Freeman, N., Chen, Z., Horenstein, J., Weber, A., and Field, J. An actin monomer binding activity localizes to the carboxyl half of the Saccharomyces cerevisiae cyclase associated protein. J. Biol. Chem. 270: 5680-5685, 1995.
Freeman, N., Lila, T., Mintzer, K., Chen, Z., Pahk, A.J., Ren, R., Drubin, D.G., and Field, J. A conserved proline rich region of the Saccharomyces cerevisiae cyclase associated protein binds SH3 domains and modulates cytoskeletal localization. Mol. Cell. Biol. 16: 548-556, 1996.
Tang, Y., Chen, Z., Ambrose, D., Liu, J., Gibbs, J.B., Chernoff, J., and Field, J. Kinase deficient Pak1 mutants inhibit Ras transformation of Rat-1 fibroblasts. Mol. Cell. Biol. 17: 4454-4464, 1997.
Tang, Y., Marwaha, S., Rutkowsky, J.L., Tennekoon, G.I., Phillips, P.C., and Field, J. A Role for Pak in Schwann cell transformation. Proc. Natl. Acad. Sci. USA, 95: 5139-5144, 1998.
Tang, Y., Yu, J., and Field, J. Signals from the Ras, Rac, and Rho GTPases converge on the Pak protein kinase in Rat-1 fibroblasts. Mol. Cell Biol. 19: 1881-1891, 1999.
Yu, J., Wang C., Palmieri, S.J., Haarer, B.K., and Field, J. A cytoskeletal localizing domain in the cyclase associated protein, CAP/Srv2p, regulates access to a distant SH3 binding site. J. Biol. Chem., in press.
