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Associate Professor, Cell Biology Director of Graduate Studies |
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Phone: (203) 737-2746 Fax: (203) 785-7446 e-mail: carl.hashimoto@yale.edu |
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Department of Cell Biology <Courier Address> |
Proteolysis drives a wide range of biological processes from the cell cycle to embryonic patterning, and is thought to mediate complex brain functions such as learning and memory. Not surprisingly, then, dysfunction in proteolysis is associated with many human disorders, including cancer and dementia. My laboratory is generally interested in cellular and developmental processes involving the proteolytic enzymes known as serine proteases and their inhibitors called serpins.
Serine proteases are known to function in tightly regulated cascades as seen in blood coagulation. Using molecular and genetic approaches, we are currently investigating serine proteases that may also function in a cascade to activate homeostatic mechanisms upon tissue injury or infection. Ultimately, we would like to understand how such cascades are triggered by environmental cues such as a wound.
Serpins inactivate serine proteases by an interesting mechanism in which they act as a suicide substrate to trap their target in a tight complex. Interestingly, certain serpin mutations are known to cause serpin aggregation in diverse pathologies such as cirrhosis, thrombosis, and neural degeneration. Our current focus is on serpins that regulate developmental and immune signaling. We are also exploring genetic strategies to revert disease phenotypes associated with serpin aggregation.
Selected Publications
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Hashimoto C, Kim DR, Weiss LA, Miller JW, Morisato D. (2003) Spatial regulation of developmental signaling by a serpin. Dev Cell. 5: 945-950.
Richer MJ, Juliano L, Hashimoto C, Jean F. (2003) Serpin mechanism of hepatitis C virus NS3 protease inhibition: Induced-fit as a mechanism for narrow specificity. J Biol Chem. 279: 10222-10227.
Richer MJ, Keays CA, Waterhouse J, Minhas J, Hashimoto C, Jean F. (2004) The Spn4 gene of Drosophila encodes a potent furin-directed secretory pathway serpin. Proc Natl Acad Sci USA. 101: 10560-10565.
