Signal Transduction and Oncogenesis

Our laboratory conducts research in the field of mammalian signal transduction, with a particular interest in the deregulated expression of small GTPases in the context of human cancer. More specifically, we have focused our research efforts on the identification and analysis of those signaling pathways that are regulated by members of the RhoGEF family. Although RhoGEFs are best known for their ability to regulate the actin cytoskeleton, they can also influence transcriptional activity and directly stimulate entry into the cell cycle. At least two members of the RhoGEF family, LARG and Bcr, contribute directly to rearrangements that are the causative agents of human leukemias, and a third member of the family has been identified at a common provirus integration site in murine B cell and myeloid leukemias. Additional disorders attributed to disruptions in members of this family include the developmental disorder faciogenital dysplasia, sporadic X-linked mental retardation, and amyotrophic lateral sclerosis. Central to our understanding of how RhoGEFs mediate this wide variety of clinical disorders will be our ability to determine how they interact with regulatory factors, and our ability to identify downstream signaling pathways that are responsible for the transformed phenotype.

Selected Publications

• Cheng, L., Mahon, G.M., Kostenko, E., and Whitehead, I.P. (2004) Pleckstrin homology domain-mediated activation of the Rho-specific guanine nucleotide-exchange factor Dbs by Rac1. J. Biol. Chem. 279: 12786-93.
  
  
• Mahon, G.M., Wang, Y., Korus, M., Kostenko, E., Cheng, L., Sun, T., Arlinghaus, R.B., and Whitehead, I.P. (2003) The c-Myc oncoprotein interacts with Bcr. Curr. Biol., Current Biology, 13, 437-441.
  
  
• Cheng, L., Rossman, K., Mahon, G.M., Worthylake, D.K., Korus, M., Sondek, J., and Whitehead, I.P. (2002) RhoGEF specificity mutants implicate RhoA as a target for Dbs transformation. Mol. Cell. Biol. 22: 6895-6905.