Dave Roberts
2005-Present |
A model system
to study the tumor suppressor APC and its role in Wnt regulation |
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Cancer results from alterations in normal cell behavior that are ultimately manifested, in part, as unregulated cell proliferation and protection from apoptosis. At the molecular level, these are frequently caused by changes in signal transduction pathways that confer cells with cancerous properties. To truly understand the bases of cancer, we must first understand the normal role(s) of the proteins involved in these signal transduction pathways. The tumor suppressor APC (adenamotous polyposis coli) and the oncogene ß-catenin (ß-cat) are key components of the Wg/Wnt pathway. Truncations in APC are the single most common cause of colon cancer in humans, occurring in greater than 80% of all colon cancers. APC binds ß-cat, which is the key effector protein of Wg/Wnt signaling, and activating mutations in ß-cat also cause cancer. |
| Studies investigating the APC and b-cat interaction ultimately led to a model that APC negatively regulates Wg/Wnt signaling by contributing to a multi-protein complex that phosphorylates ß-cat. Phosphorylated ß-cat is then targeted for ubiquitin-mediated proteolytic degradation, preventing ß-cat from activating Wg/Wnt responsive genes such as myc. Although a substantial amount of evidence supports a role for APC in the ß-cat destruction complex, many questions still remain regarding how APC functions in the complex. In addition, little is known about how ß-cat is targeted for degradation once it is phosphorylated by the destruction complex. To address these questions, I will investigate APC and the ß-cat homolog, Armadillo (Arm), in the fruit fly Drosophila melanogaster. By studying these proteins in Drosophila, we take advantage of the speed of this model system, as well as the wealth of reagents available to perform genetic, cell biological, and biochemical experiments. I am investigating the mechanisms that regulate Arm/ß-cat degradation. I am carrying out a structure/function experiment of Drosophila APC2. I will then use the information garnered from this analysis to evaluate models of APC function in the destruction complex. Second, I am exploring the possibility that APC transfers phosphorylated ß-cat to E3 ubiquitin ligases that target Arm/ß-cat for degradation. Finally, I am working to define the molecular components present in the E3 ubiquitin ligases that target Arm/ß-cat for degradation. | |
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Publications Roberts, D.M., Slep, K.C., and Peifer, M. (2007). It takes more than two to tango: Dishevelled polymerization and Wnt signaling. Nature Structural and Molecular Biology, in press. Price, M.H.*, Roberts, D.M.*, McCartney, B.M., Jezuit, E, and Peifer, M. (2006). Cytoskeletal dynamics and cell signaling during planar polarity establishment in the Drosophila embryonic denticle. Journal of Cell Science, in press. (*=co-first authors) Roberts, D.M, Anderson, A.L, Hidaka, M, Swetenburg, R.L, Patterson, C, Stanford, W.L, Bautch, V.L. (2004) A vascular gene trap screen defines RasGRP3 as an angiogenesis-regulated gene required for the endothelial response to phorbol esters. Mol Cell Biol. 24:10515-28. Roberts, D.M, Kearney, J.B, Johnson, J.H, Rosenberg,
M.P, Kumar, R, Bautch, V.L. (2004) |