Vande Pol Lab Research Opportunities
Associate Professor of Pathology
How viruses, particularly papillomaviruses, can cause cancer.
Papillomaviruses cause cervical cancer, anogenital cancers and many head and neck cancers because they express two virally encoded oncoproteins, E6 and E7.
We have identifed cellular proteins that interact with E6 oncoproteins that cause human cancers as well as with E6 proteins from papillomavirus types that cause benign epithelial proliferations. Previously, we identified paxillin as a target for viral transformation by the BPV-1 E6 oncoprotein (paxillin is an adapter molecule involved in the regulation of integrin signaling, and the activation of tyrosine kinase signaling pathways and transformation (4-8)), and more recently we identified cellular transcription factors, MAML1 and MAML3, that are critically important mediators of Notch signaling and that associate with E6 proteins; we are interested in examining how Notch signaling is integrated into the papillomavirus life cycle in keratinocytes.
A second related project examines new targets of cancer associated papillomavirus E6 oncoproteins that contain PDZ domains that regulate cell polarity. One such protein is the tyrosine phosphatase PTPN3. Using mass spectrometry and proteomics techniques we discovered that E6 can interact with PTPN3 and then catalyze the degradation of PTPN3. This is the first example of an E6 oncoprotein directly manipulating phosphotyrosine metabolism (3). We are trying at this point to identify those additional E6-PDZ domain interactions that are critical for the virus life cycle and those that may be implicated in non-virally implicated human cancers.
In recent years, we initiated a collaboration with colleagues in Strasbourg, France (Dr. Gilles Trave and collaborators) to obtain the structure of the E6 oncoprotein. By pursuing a novel experimental approach my colleagues in France have obtained a crystal structure of E6 shown above. We are using this structure to obtain insights to E6 function in the targeted degradation of p53 and precisely define the structure-function relationships of E6 in papillomavirus transformation. This ongoing work is not yet published.
- How do viral oncoproteins manipulate cell survival signaling and cell death, and can this be manipulated to gain therapeutic advantage in virus caused tumors?
- How does Notch signaling regulate the replication cycle of papillomaviruses?
- How do polarity proteins inside the cell connect to transmembrane tumor suppressors to inhibit cell invasion?
What general knowledge and techniques would you would learn during a rotation:
- How viral oncoproteins are models for the cellular targets important in both virus caused and non-virus caused cancers.
- Techniques in proteomics and cell biology, including mass spectrometry, production of recombinant viruses to express and knock down cellular protein expression, cell culture, gene expression analysis.
- Bohl, J., N. Brimer, C. Lyons, and S. B. Vande Pol. 2007. The stardust family protein MPP7 forms a tripartite complex with LIN7 and DLG1 that regulates the stability and localization of DLG1 to cell junctions. J Biol Chem 282:9392-400.
- Brimer, N., C. Lyons, A. E. Wallberg, and S. B. Vande Pol. 2011. Papillomavirus E6 oncoproteins associate with MAML1 to repress transactivation and Notch signaling. Oncogene In Press.
- Jing, M., J. Bohl, N. Brimer, M. Kinter, and S. B. Vande Pol. 2007. Degradation of tyrosine phosphatase PTPN3 (PTPH1) by association with oncogenic human papillomavirus E6 proteins. J Virol 81:2231-9.
- Vande Pol, S. B., M. C. Brown, and C. E. Turner. 1998. Association of Bovine Papillomavirus Type 1 E6 oncoprotein with the focal adhesion protein paxillin through a conserved protein interaction motif. Oncogene 16:43-52.
- Wade, R., J. Bohl, and S. Vande Pol. 2002. Paxillin null embryonic stem cells are impaired in cell spreading and tyrosine phosphorylation of focal adhesion kinase. Oncogene 21:96-107.
- Wade, R., N. Brimer, C. Lyons, and S. Vande Pol. 2010. Paxillin enables attachment-independent tyrosine phosphorylation of focal adhesion kinase and transformation by RAS. J Biol Chem 286:37932-44.
- Wade, R., N. Brimer, and S. Vande Pol. 2008. Transformation by bovine papillomavirus type 1 E6 requires paxillin. J Virol 82:5962-6.
- Wade, R., and S. Vande Pol. 2006. Minimal features of paxillin that are required for the tyrosine phosphorylation of focal adhesion kinase. Biochem J 393:565-73.