Name: David Kimelman
Position: Professor of Biochemistry
One area of major interest is the role of the Wnt pathway in regulating the formation of the head and dorsal axis in the frog embryo in response to the entry of the sperm. We have determined several of the key intracellular interactions that regulate this pathway including the kinase GSK3 and a novel inhibitor of GSK3 (GBP) that we cloned in a 2-hyrid screen. Together with Randall Moon's group (Pharmacology), we showed that GSK3 acts by phosphorylating the protein ß-catenin causing it to be degraded. We showed that ß-catenin works to activate the transcription of the siamois gene, which is the master regulator of head and dorsal axis formation. In our recent work, we found that GBP is transported in the frog egg by binding kinesin, demonstrating that GBP acts as an interface between the sperm directed microtubule network and the regulators of ß-catenin. Together with Dr. Wenqing Xu's group (Biostructure), we have used crystallography to understand the interactions between different proteins in the Wnt pathway, and used this structural information to test new hypotheses about the workings of this pathway, and to reveal potential drug targets since misregulation of ß-catenin levels leads to a variety of cancers. We recently determined the structures of ß-catenin bound to Axin and to APC, which are key members of the complex of proteins that regulates ß-catenin levels. This structure suggested a new mechanism for ß-catenin turnover within the complex. Using biochemical and structural approaches, we are continuing to analyze this complex. In zebrafish, we have been working to understand how intercellular signals pattern the formation of the mesoderm, taking advantage of the genetics avaigrouple in this system. We are particularly focused on the role of Bmp in regulating the formation of the tail, and the downstream genes regulated by Bmp signals. We have also discovered the molecular nature of two important patterning mutations, floating head and spadetail. Floating head mutants lack the notochord, and are due to a mutation in a homeobox transcription factor. Spadetail mutants lack the trunk muscle and are due to a mutation in a T-box transcription factor. We are actively continuing our studies on the interplay of intercellular signals and transcription factors in forming the trunk and tail.
Department of Biochemistry
University of Washington
Web Page: http://depts.washington.edu/kimellab/Home.html
Phone: 206 543-5730
Fax: 206 616-8676