The Wnt family of proteins are secreted signaling molecules that regulate a number of critical developmental processes, including cellular proliferation and differentiation. Moreover, aberrant activation of the Wnt signaling pathway has been shown to be an important component in oncogenesis. Wnt signaling is very complex and is initiated by a family of transmembrane heptahelical receptors known as Frizzled, which are most closely related to the family of G protein coupled-receptors. Despite evidence implicating G proteins in Wnt/Frizzled signal transduction, the precise mechanism by which Frizzled receptors choose downstream targets and transmit signals to them is still unclear. In this application, I propose to identify specific Frizzled/G protein interactions to test the hypothesis that Frizzled receptors are, in fact, G protein-coupled receptors. In addition, I will attempt to define the role of G proteins in determining Wnt/Frizzled signaling pathway choices and in linking Frizzled to known downstream target molecules such as Axin. The proposed project will be undertaken with the mentorship of Dr. Patrick J. Casey and Dr. Robert J. Lefkowitz and with the support of the Department of Pathology at Duke University. My background in protein biochemistry and G protein signaling provides a solid foundation for initiating these studies. This award will allow me to develop skills necessary to progress to the study of more biological aspects of cell regulation and will facilitate my transition to an independent investigator.
|Rossol-Allison, Jessica; Stemmle, Laura N; Swenson-Fields, Katherine I et al. (2009) Rho GTPase activity modulates Wnt3a/beta-catenin signaling. Cell Signal 21:1559-68|
|Stemmle, Laura N; Fields, Timothy A; Casey, Patrick J (2006) The regulator of G protein signaling domain of axin selectively interacts with Galpha12 but not Galpha13. Mol Pharmacol 70:1461-8|
|Kelly, Patrick; Moeller, Benjamin J; Juneja, Juhi et al. (2006) The G12 family of heterotrimeric G proteins promotes breast cancer invasion and metastasis. Proc Natl Acad Sci U S A 103:8173-8|
|Fields, Timothy A; McCall, Shannon J; Reams, B Diane et al. (2005) Pulmonary embolization of microcrystalline cellulose in a lung transplant recipient. J Heart Lung Transplant 24:624-7|
|Kimple, Michelle E; Nixon, Andrew B; Kelly, Patrick et al. (2005) A role for G(z) in pancreatic islet beta-cell biology. J Biol Chem 280:31708-13|
|Szczech, Lynda Anne; Gupta, Samir K; Habash, Ramez et al. (2004) The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection. Kidney Int 66:1145-52|