Specific Clinical/Research Interests:
How the processes of growth and proliferation are regulated and how loss of that regulation leads to cancer, with a special emphasis on regulation by the ubiquitin pathway.

Summary of Research Studies:
My lab will combine in vitro biochemical methods and in vivo Drosophila genetic analysis to understand how the processes of growth and proliferation and regulated, and how loss of that regulation results in cancer. I am pursuing the study of two main pathways: (1) an emerging tumor suppressor pathway called the "hippo pathway" and (2) the ubiquitin pathway.

(1) The hippo pathway. Hippo is a kinase that acts in a pathway with the known tumor suppressors salvador and warts. Recently, this pathway has also been connected to the merlin/nf2 tumor suppressor gene that is mutated in Neurofibromatosis type 2. Because the hippo pathway has only recently been discovered, little is known about its regulation or targets. The mammalian homologs of hippo (Mst1 and Mst2) were originally identified as stress response kinases, and the yeast homolog is involved in the Mitotic Exit Network. I am interested identifying additional targets of the hippo and warts kinases that may, themselves, represent novel tumor suppressor genes or oncogenes. My lab has completed a biochemical screen to identify downstream targets of this pathway and we are now evaluating the role of candidate targets as important effectors of the hippo pathway's tumor suppressor role.

(2) The ubiquitin pathway. Ubiquitin (a 76 amino acid protein highly conserved from yeast to humans) serves as a tag to direct proteins to different fates, such as endocytosis or degradation. The ubiquitin pathway regulates key steps in cell cycle progression, signal transduction, and growth. Mutations in its regulators, components, and targets occur in cancer and neurodegenerative diseases. Because altering the levels of ubiquitin pathway substrates can lead to cancer, identifying additional regulators and substrates is of interest. Using in vivo Drosophila characterization, my lab has discovered that signaling through the Ras pathway is elevated when ubiquitination is impaired. It is widely accepted that Receptor Tyrosine Kinases (RTKs) are regulated by ubiquitination, and our studies now suggest that the ubiquitination of Ras itself is also important to regulate proper growth and proliferation. We are now studying the biological role of Ras ubiquitination, and we intend to identify and characterize the Ras ubiquitin ligase.

The Pfleger Laboratory