Karin List, Ph.D.
Assistant Professor
Department of Pharmacology
Barbara Ann Karmanos Cancer Institute
Wayne State University School of Medicine
540 East Canfield, Room 6332
Detroit, Michigan 48201

Phone: 313-577-1034
E-mail: klist@med.wayne.edu


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.

Fig 1. 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.




Research papers

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, John P. Hobson, Alfredo Molinolo and Thomas H. Bugge. Co-localization of the channel activating protease prostasin/(CAP1/PRSS8) with its candidate activator, matriptase. 
J. Cell. Physiol. (2007), 213(1):237-45

Roman Szabo, Alfredo Molinolo, Karin List and Thomas H. Bugge. Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development.
Oncogene (2007), 26(11):1546-56

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

Timo Piironen, Birgitte Laursen, Karin List, Henrik Gårdsvoll, Jesper Pass, Michael Ploug, Keld Danø and Gunilla Høyer-Hansen. Specific immunoassays for the detection of intact and cleaved  forms of the urokinase receptor. Clin. Chem. (2004), 50(11):2059-68

Karin List, Roman Szabo, Phillip W. Wertz, Julie Segre, Christian  C. Haudenschild, Soo Y. Kim, and Thomas H. Bugge.  Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1.  J. Cell. Biol. (2003), 163(4): 901-10

Niels Behrendt, Karin List, Peter A. Andreasen and Keld Danø. The pro-urokinase - plasminogen activation system in the presence of serpin-type inhibitors and the urokinase receptor: Rescue of activity through reciprocal pro-enzyme activation. Biochem J. (2003), 371:277-87

Lars H. Engelholm, Karin List, Sarah Netzel-Arnett, Edna Cukierman,  David J. Mitola, Hannah Aaronson, Lars Kjøller, Kenneth. M. Yamada, Dudley Strickland, Kenn Holmbeck, Keld Danø,  Henning Birkedal-Hansen, Niels Behrendt and  Thomas H. Bugge. uPARAP/Endo180 is a fibroblast adhesion and internalization receptor for collagen. J. Cell Biol. (2003), 160(7):1009-15

Alexandra Makarova, Irina Mikhailenko, Thomas H. Bugge, Karin List, Daniel A. Lawrence and Dudley K. Strickland. The LDL receptor-related protein modulates protease activity in the brain by mediating the cellular internalization of both neuroserpin and neuroserpin: tPA complexes. J. Biol. Chem. (2003), 278(50):50250-8

Karin List, Christian C. Haudenschild, Roman Szabo, WanJun Chen, Sharon M. Wahl, William Swaim, Lars H. Engelholm, Niels Behrendt and Thomas H. Bugge. Matriptase/MT-SP1 is required for postnatal survival, epidermal barrier function, hair follicle development, and thymic homeostasis. Oncogene (2002), 21(23):3765-79

Karin List, Ole N. Jensen, Thomas H. Bugge,  Leif R. Lund, Michael Ploug, Keld Danø and Niels Behrendt. Plasminogen-independent  initiation of the  pro-urokinase activation cascade in vivo.  Activation of pro-urokinase by glandular kallikrein (mGK-6) in plasminogen deficient mice. Biochemistry (2000), 39(3): 508-515

Karin List, Gunilla Høyer-Hansen, Ebbe Rønne, Keld Danø and Niels Behrendt. Different mechanisms are involved in the antibody mediated inhibition of ligand binding to the urokinase receptor: A study based on biosensor technology. Journal of Immunological Methods (1999), 222: 123-133

Reviews

Thomas H. Bugge, Karin List, and Roman Szabo.  Matriptase-dependent cell surface proteolysis in epithelial development and pathogenesis. Front. Biosci. (2007), 12:5060-70

Karin List, Thomas H. Bugge, and Roman Szabo. Matriptase: Potent proteolysis on the cell surface. Mol. Med. (2006), 12(1-3): 1–7

Book Chapter

Karin List and Thomas H. Bugge (2007) Physiological and pathological functions of type II transmembrane serine proteases: Lessons from transgenic mouse models and human disease-associated mutations. The Cancer Degradome-Proteases and Cancer Biology. ed. Dylan Edwards, Springer, New York, In Press.