Cells; Cell Biology; Education, Medical; Endocrine System Diseases; Genetics; Molecular Biology; Tissues; Developmental Biology; Serpins; Neurodegenerative Diseases; Intercellular Signaling Peptides and Proteins; Proteolysis
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 that are regulated by proteolysis.
Specialized Terms: Proteolysis; Serpins; Intercellular signaling; Morphogenesis; Disease modeling; Drosophila molecular genetics
Extensive Research Description
The coordinated action of proteases and their inhibitors plays an important role in morphogenesis and function of many organs. Disruption of the protease-inhibitor balance is associated with diverse pathologies including cancer. My laboratory is particularly interested in biological processes and diseases involving protease inhibitors known as serpins, which uniquely inactivate proteases by acting as a suicide substrate to trap their target in a tight complex. Perhaps the best known serpins function in blood clotting, inflammation, and other host defense reactions; however, the biological function of many more serpins is unknown. We are using genetic and functional genomic approaches to define biological roles for serpins. These studies have already identified a serpin important for morphogenesis and tissue remodeling events during development. Diverse pathologies such as liver cirrhosis, thrombosis, and neurodegeneration are associated with mutant serpins that spontaneously polymerize to form intracellular inclusions. We are interested in understanding how cells deal with these intracellular inclusions and in exploring genetic strategies to revert disease phenotypes resulting from serpin polymerization.
Identifying a serpin-regulated proteolytic cascade involved in innate immunity.
Understanding a cell death pathway controlled by a serpin.
Exploring the role of insulin degrading enzyme in insulin signaling.
A serpin that regulates immune melanization in the respiratory system of Drosophila.
Tang, H., Kambris, Z., Lemaitre, B., and Hashimoto, C. (2008) A serpin that regulates immune melanization in the respiratory system of Drosophila. Dev. Cell 15, 617-626.
Two proteases defining a melanization cascade in the immune system of Drosophila.
Tang, H., Kambris, Z., Lemaitre, B., and Hashimoto, C. (2006). Two proteases defining a melanization cascade in the immune system of Drosophila. J. Biol. Chem. 281:28097-28104.
The Spn4 gene of Drosophila encodes a potent furin-directed secretory pathway serpin.
Richer, M. J., Keays, C. A., Waterhouse, J., Minhas, J., Hashimoto, C. and Jean, F. (2004) The Spn4 gene of Drosophila encodes a potent furin-directed secretory pathway serpin. Proc. Natl. Acad. Sci. USA 101, 10560-10565.image
Spatial regulation of developmental signaling by a serpin.
Hashimoto, C., Kim, D.R., Weiss, L.A., Miller, J.W. and Morisato, D. (2003) Spatial regulation of developmental signaling by a serpin. Dev. Cell 5, 945-950.
Full List of PubMed Publications
- Hyun J, Hashimoto C: Physiological effects of manipulating the level of insulin-degrading enzyme in insulin-producing cells of Drosophila. Fly (Austin). 2011 Jan-Mar; 2011 Jan 1. PMID: 21212741
- Tang H, Kambris Z, Lemaitre B, Hashimoto C: A serpin that regulates immune melanization in the respiratory system of Drosophila. Dev Cell. 2008 Oct. PMID: 18854145
- Tang H, Kambris Z, Lemaitre B, Hashimoto C: Two proteases defining a melanization cascade in the immune system of Drosophila. J Biol Chem. 2006 Sep 22; 2006 Jul 21. PMID: 16861233
- Hashimoto C, Kim DR, Weiss LA, Miller JW, Morisato D: Spatial regulation of developmental signaling by a serpin. Dev Cell. 2003 Dec. PMID: 14667416
- Turcotte CL, Hashimoto C: Evidence for a glycosaminoglycan on the nudel protein important for dorsoventral patterning of the drosophila embryo. Dev Dyn. 2002 May. PMID: 11984873
- Otake LR, Scamborova P, Hashimoto C, Steitz JA: The divergent U12-type spliceosome is required for pre-mRNA splicing and is essential for development in Drosophila. Mol Cell. 2002 Feb. PMID: 11864616