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Karin List, Ph.D. |
RESEARCH INTERESTS:
Extracellular proteases can degrade extracellular matrix proteins and reshape the tissue microenvironment as well as cleave and activate signaling molecules such as growth factors and their receptors. These processes are essential for normal physiological tissue development, remodeling, and repair. On the flip side, tissue malfunction and tissue destruction due to dysregulated extracellular proteolysis characterize many pathological conditions including cancer. Extracellular proteolytic processes are critically involved in tumor growth, invasion, and dissemination of cancer cells to other organs.
Proteolysis in the extracellular/pericellular environment is mediated by about 300 different proteases in humans, of which approximately one-third are directly anchored to the plasma membrane. We are particularly interested in a family of cell-surface-anchored proteases: the type II transmembrane serine proteases (TTSPs) and their role in tissue remodeling during epithelial development and carcinogenesis.
Epithelial expression of the type II transmembrane serine protease matriptase. A knock-in mouse with a promoterless β-galactosidase marker gene inserted into the matriptase locus is used as a unique tool for assessing endogenous matriptase expression in various tissues. Matriptase (cyan/green) is expressed in the epithelium of lung, mammary gland, and salivary gland as determined by X-gal staining of mouse organ whole mounts.
Understanding the physiological role of extracellular proteases in tissue development and homeostasis is important in order to pinpoint how dysregulated proteolysis can cause or contribute to cancer progression. The motivation behind parallel investigations of normal physiology and pathology is the idea that carcinogenesis often involves pathways, including proteolytic pathways, that are important in normal development and have gone awry in cancer. Generation and characterization of mouse models, including models of human cancer, play an integral role in our research. We use knock-out and transgenic mice for selected extracellular proteases and protease inhibitors as unique tools to identify critical proteolytic pathways in health and disease.
Current Lab Personnel:
Chao Becky Wang, B.S. – Research Assistant (cbwang@med.wayne.edu))
Selected Recent Publications:
- Karin List, Brooke Currie, Tiffany C. Scharschmidt, Roman Szabo, Jessica Shireman, Alfredo Molinolo, Benjamin F. Cravatt, Julia Segre, and Thomas H. Bugge Autosomal Ichthyosis with Hypotrichosis Syndrome displays low matriptase proteolytic activity and is phenocopied in ST14 hypomorphic mice. J. Biol. Chem. (2007), 282(50):36714-23
- Karin List, Roman Szabo, Alfredo Molinolo and Thomas H. Bugge. Delineation of matriptase protein expression by enzymatic gene trapping suggests diverging roles in barrier function, hair formation, and squamous cell carcinogenesis. Am. J. Pathol. (2006), 168(5):1513-25
- Sarah Netzel-Arnett, Brooke M. Currie, Roman Szabo, Chen Yong-Lin, Li-Mei Chen, Karl X. Chai, Toni M. Antalis, Thomas H. Bugge, and Karin List. Evidence for a matriptase-prostasin proteolytic cascade regulating terminal epidermal differentiation. J. Biol. Chem. (2006), 281(44):32941-5
- Karin List, Roman Szabo, Alfredo Molinolo, Virote Sriuranpong, Vivien Redeye, Tricia Murdock, Beth Burke, Boye Schnack Nielsen, J. Silvio Gutkind and Thomas H. Bugge. Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation. Genes & Development, (2005), (16):1934-50
- Karin List, Thomas H. Bugge, and Roman Szabo. Matriptase: Potent proteolysis on the cell surface. Mol. Med. (2006), 12(1-3): 1–7
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