Professor, Department of Molecular & Cell Biology
72 East Newton Street
Boston, MA 02118-2394 USA
MD, Semmelweis University, Budapest, Hungary, 1988
PhD, Semmelweis University, Budapest, Hungary, 1994
Post-doctoral training: Howard Hughes Medical Institute at the University of California Los Angeles, 1990–1993
The Scripps Research Institute, 1993–1995
The Role of Proteases in Pancreatitis. Our laboratory studies how various proteases and their inhibitors in the pancreas contribute to the pathogenesis of pancreatitis. Pancreatitis is believed to occur due to inappropriate, intrapancreatic activation of digestive enzymes (e.g. trypsin, chymotrypsin, elastase), which are normally synthesized and stored in their inactive forms in the pancreas. Our long-term objectives are to understand the molecular mechanisms of human pancreatitis, using genetically determined pancreatitis (e.g. hereditary pancreatitis) as a biochemical model. The main focus of our research program is to provide biochemical evidence that genetic alterations in the three human trypsinogen isoforms (PRSS1, PRSS2 and PRSS3 genes) and the pancreatic secretory trypsin inhibitor (SPINK1 gene) can significantly influence the susceptibility for the development of pancreatitis. Thus, gain-of-function mutations in cationic trypsinogen can cause pancreatitis, while loss of function mutations in anionic trypsinogen can actually protect against pancreatitis. Loss of the inhibitory function of SPINK1 either due to mutations or to degradation by mesotrypsin can represent another risk factor for pancreatitis onset. The following specific projects are studied. (1) The role of human mesotrypsin in pancreatitis. Mesotrypsin is a unique protease specialized for the degradation of trypsin inhibitors. Premature mesotrypsinogen activation might lower protective SPINK1 levels in the pancreas and contribute to the pathogenesis of pancreatitis. (2) Characterization of pancreatitis-associated cationic trypsinogen (PRSS1) mutants. Identification of novel mutation-dependent biochemical defects that lead to hereditary pancreatitis (3) Functional analysis of anionic trypsinogen (PRSS2) mutants that afford protection against pancreatitis. The concept that loss-of-function trypsinogen mutations can protect against pancreatitis provides independent evidence for the central role of trypsin in this disease. (4) Identification of the disease-causing biochemical defects in pancreatitis-associated SPINK1 mutants.
Szmola, R., Sahin-Tóth, M. (2010). Uncertainties in the classification of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated mutations. J Med Genet 47:348–350.
Szmola, R., Sahin-Tóth, M. (2010). Pancreatitis-associated chymotrypsinogen C (CTRC) mutant elicits endoplasmic reticulum stress in pancreatic acinar cells. Gut 59, 365–372.
Wartmann, T., Mayerle, J., Kähne, T., Sahin-Tóth, M., Ruthenbürger, M., Matthias, R., Kruse, A., Reinheckel, T., Peters, C., Weiss, F. U., Sendler, M., Lippert, H., Schulz, H. U., Aghdassi, A., Dummer, A., Teller, S., Halangk, W., Lerch, M. M. (2010). Cathepsin L inactivates human trypsinogen, whereas cathepsin L-deletion reduces the severity of pancreatitis in mice. Gastroenterology 138, 726–737.
Kereszturi, E., Sahin-Tóth, M. (2009). Intracellular autoactivation of human cationic trypsinogen mutants causes reduced trypsinogen secretion and acinar cell death. J Biol Chem 284, 33392–33399.
Medveczky, P., Szmola, R., Sahin-Tóth, M. (2009). Proteolytic activation of human pancreatitis associated protein is required for peptidoglycan binding and bacterial aggregation. Biochem J 420, 335–343.
Kereszturi, E., Szmola, R., Kukor, Z., Simon, P., Ulrich, Weiss F., Lerch, M. M., Sahin-Tóth, M. (2009). Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. Hum Mutat 30, 575–582.
Rónai, Z., Witt, H., Rickards, O., Destro-Bisol, G., Bradbury, A. R., Sahin-Tóth, M. (2009). A common African polymorphism abolishes tyrosine sulfation of human anionic trypsinogen (PRSS2). Biochem J 418, 155–161.
Kereszturi, E., Király, O., Sahin-Tóth, M. (2009). Minigene analysis of intronic variants in common SPINK1 haplotypes associated with chronic pancreatitis. Gut 58, 545–549.
Rosendahl, J., Witt, H., Szmola, R., Bhatia, E., Ózsvári, B., Landt, O., Schulz, H-U, Gress, T. M., Pfützer, R., Löhr, M., Kovacs, P., Blüher, M., Stumvoll, M., Choudhuri, G., Hegyi, P., te Morsche, R. H. M., Drenth, J. P. H., Truninger, K., Macek Jr., M., Puhl, G., Witt, U., Schmidt, H., Büning, C., Ockenga, J., Kage, A., Groneberg, D. A., Nickel, R., Berg, T., Wiedenmann, B., Bödeker, H., Keim, V., Mössner, J., Teich, N., Sahin-Tóth, M. (2008). Chymotrypsin C (CTRC) alterations that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet 40, 78–82.
Szmola, R., Sahin-Tóth, M. (2007). Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: Identity with Rinderknecht’s enzyme Y. Proc Natl Acad Sci USA 104, 11227–11232.