B. S. Bowling Green State University
Ph.D. University of North Carolina at Chapel Hill
A model system to study the tumor suppressor APC and its role in Wnt regulation
To properly orchestrate the dramatic events that occur during development, it is essential that cells communicate with their neighbors through the use of cell signaling pathways. While many of these signaling pathways play critical roles in the development of an organism, inappropriate activation of these pathways frequently results in cancer.
The Wnt signaling pathway is one such pathway that contributes to both normal development and cancer. Wnt signaling plays essential roles in development such as defining cell fate decisions. However, loss-of-function mutations in an important molecular player of the Wnt pathway called Adenomatous Polyposis Coli (APC) inappropriately activate the pathway and frequently lead to cancer. In fact, mutations in APC are responsible for most cases of the inherited colon cancer syndrome, familial adenomatous polyposis, and overall are responsible for greater than 80% of all colon cancer cases. Therefore, understanding APC’s function in Wnt signaling is crucial to understanding how it contributes to cancer.
It is now clear that APC participates in Wnt signaling by contributing to a multi-protein complex, called the “destruction complex.” Despite intense interest in APC and Wnt signaling in general, the molecular role of APC in the destruction complex remains unknown. My current work uses both fruit flies and cultured colon cancer cell lines to explore APC’s mechanism of action. Potential projects in the lab include:
- defining the pieces of APC that are essential for its function in Wnt signaling
- identifying novel protein partners that work with APC
- investigating how APC interacts with known members of the destruction complex.
These projects will address current models of APC function, and may ultimately help other researchers design better therapeutics to treat colon cancer. I am looking for motivated, enthusiastic students to join my research group, and encourage students interested in conducting independent research in my lab to contact me.
Current Funding: AREA grant from the National Institutes of Health (R15 GM107796-01).
F&M student co-authors indicated by *.
Poulton JS, Mu FW, Roberts DM, Peifer M. APC2 and Axin promote mitotic fidelity by facilitating centrosome separation and cytoskeletal regulation. Development. 2013; Oct;140(20):4226-4236.
Roberts DM, Pronobis MI, Poulton JS, Kane EG*, Peifer M. Regulation of Wnt signaling by the tumor suppressor adenomatous polyposis coli does not require the ability to enter the nucleus or a particular cytoplasmic localization. Mol Biol Cell. 2012; Jun;23(11):2041-56.
Roberts DM, Pronobis MI, Alexandre KM, Rogers GC, Poulton JS, Schneider DE, Jung KC, McKay DJ, Peifer M. Defining components of the ß-catenin destruction complex and exploring its regulation and mechanisms of action during development. PLoS One. 2012;7(2):e31284.
Roberts DM, Pronobis MI, Poulton JS, Waldmann JD, Stephenson EM, Hanna S*, Peifer M. Deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling. Mol Biol Cell. 2011 Jun 1;22(11):1845-63.
Randhawa PK, Rylova S, Heinz JY, Kiser S, Fried JH, Dunworth WP, Anderson AL, Barber AT, Chappell JC, Roberts DM, Bautch VL. The Ras activator RasGRP3 mediates diabetes-induced embryonic defects and affects endothelial cell migration. Circ Res. 2011 May 13;108(10):1199-208.
Rogers GC, Rusan NM, Roberts DM, Peifer M, Rogers SL. The SCF Slimb ubiquitin ligase regulates Plk4/Sak levels to block centriole reduplication. J Cell Biol. 2009 Jan 26;184(2):225-39.
Roberts DM, Slep KC, Peifer M. It takes more than two to tango: Dishevelled polymerization and Wnt signaling. Nat Struct Mol Biol. 2007 Jun;14(6):463-5.
Price MH#, Roberts DM#, McCartney BM, Jezuit E, Peifer M. Cytoskeletal dynamics and cell signaling during planar polarity establishment in the Drosophila embryonic denticle. J Cell Sci. 2006 Feb 1;119(Pt 3):403-15. # co-first author manuscript.
Roberts DM, Anderson AL, Hidaka M, Swetenburg RL, Patterson C, Stanford WL, Bautch VL. A vascular gene trap screen defines RasGRP3 as an angiogenesis-regulated gene required for the endothelial response to phorbol esters. Mol Cell Biol. 2004 Dec;24(24):10515-28.
Roberts DM, Kearney JB, Johnson JH, Rosenberg MP, Kumar R, Bautch VL. The vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR-1) modulates Flk-1 (VEGFR-2) signaling during blood vessel formation. Am J Pathol. 2004 May;164(5):1531-5.