Donald F Steiner

Our laboratory studies many aspects of the biosynthesis and processing of precursor proteins of the neuroendocrine (NE) system. Current studies focus on the prohormone convertases, a 7-member family of proteolytic enzymes which function mainly in the distal secretory pathway in cells to process a wide variety of precursors. PC2 and PC1/3 are thought to be the major convertases involved in processing NE proproteins in the brain and various endocrine tissues. Their differential expression in various NE cell populations often leads to the production of differing mixtures of products derived from the same precursor, e.g., PC2 selectively releases glucagon from proglucagon in the alpha cells of the islets, while PC1/3 releases glucagon-like peptides 1 (GLP1) and 2 (GLP2) from proglucagon in the intestinal L cells. Mouse PC2 and PC1/3 gene nulls have been generated and have interesting and complex phenotypes consistent with their major roles in NE processing. We are currently using gene disruptions and other approaches to study the roles of other members of the convertase family. We are also trying to learn more about the folding and structural features of precursor proteins that facilitate their transport, sorting and processing into active products.

Other studies in the laboratory are concerned with the identification of unique gene products within the pancreatic insulin-producing beta and alpha cells that may be involved in the pathogenesis of diabetes. We are also studying the ligand binding regions in the insulin receptor a sub-unit to gain more insight into the mechanism of ligand binding and signal transduction. The evolution of the insulin superfamily of hormones and their receptors is another fascinating undertaking. In addition, we are interested in the developmental mechanisms that control the differentiation and replenishment of the beta cells with the eventual goal of developing genetically engineered surrogate beta cells for diabetes therapy.

Our laboratory studies many aspects of the biosynthesis and processing of precursor proteins of the neuroendocrine (NE) system. Current studies focus on the prohormone convertases, a 7-member family of proteolytic enzymes which function mainly in the distal secretory pathway in cells to process a wide variety of precursors. PC2 and PC1/3 are thought to be the major convertases involved in processing NE proproteins in the brain and various endocrine tissues. Their differential expression in various NE cell populations often leads to the production of differing mixtures of products derived from the same precursor, e.g., PC2 selectively releases glucagon from proglucagon in the alpha cells of the islets, while PC1/3 releases glucagon-like peptides 1 (GLP1) and 2 (GLP2) from proglucagon in the intestinal L cells. Mouse PC2 and PC1/3 gene nulls have been generated and have interesting and complex phenotypes consistent with their major roles in NE processing. We are currently using gene disruptions and other approaches to study the roles of other members of the convertase family. We are also trying to learn more about the folding and structural features of precursor proteins that facilitate their transport, sorting and processing into active products.

Other studies in the laboratory are concerned with the identification of unique...

Furuta, M., Carroll, R., Martin, S., Swift, H., Ravazzola, M., Orci, L. and Steiner, D.F. Incomplete processing of proinsulin to insulin accompanied by elevation of des-31,32 proinsulin intermediates in islets of mice lacking active PC2. J. Biol. Chem. 273:3431-3437 (1998).  

Furuta, M., Yano, H., Zhou, A., Rouill , Y., Holst, J.J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H., and Steiner, D.F. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc. Natl. Acad. Sci. USA 94:6646-6651 (1997). 

Furuta, M., Zhou, A., Webb, G., Carroll, R., Ravazzola, M., Orci, L., and Steiner, D.F. Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice. J. Biol. Chem. 276:27197-27202 (2001).  

Steiner, D.F. The prohormone convertases and precursor processing in protein biosynthesis. In: The Enzymes, Vol. XXII (eds. R.E. Dalbey and D.S. Sigman), pp. 163-198, Academic Press, New York, 2001. 

Ueda, K., Lipkind, G.M., Zhou, A., Zhu, X., Kuznetsov, A., Philipson, L., Gardner, P., Zhang, C., and Steiner, D.F. Mutational analysis of predicted interactions between the catalytic and P domains of prohormone convertase 3 (PC3/PC1). Proc. Natl. Acad. Sci. USA 100:5622-5627 (2003).  

Zhou, A., Webb, G., Zhu, X. and Steiner, D.F. Proteolytic processing in the secretory pathway. J. Biol. Chem. 274:20745-10748 (1999). 

Zhu, X., Orci, L., Carroll, R., Norrbom, C., Ravazzola, M., and Steiner, D.F. Severe block in processing of proinsulin to insulin accompanied by elevation of des-64,65 proinsulin intermediates in islets of mice lacking prohormone convertase 1/3. Proc. Natl. Acad. Sci. USA 99: 10299-10304 (2002).  

Zhu, X., Zhou, A., Dey, A., Norrbom, C., Carroll, R., Zhang, C., Laurent, V., Lindberg, I., Ugelholdt, R., Holst, J.J., and Steiner, D.F. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc. Natl. Acad. Sci. USA 99:10293-10298 (2002).  

Furuta, M., Carroll, R., Martin, S., Swift, H., Ravazzola, M., Orci, L. and Steiner, D.F. Incomplete processing of proinsulin to insulin accompanied by elevation of des-31,32 proinsulin intermediates in islets of mice lacking active PC2. J. Biol. Chem. 273:3431-3437 (1998).  

Furuta, M., Yano, H., Zhou, A., Rouill , Y., Holst, J.J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H., and Steiner, D.F. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc. Natl. Acad. Sci. USA 94:6646-6651 (1997). 

Furuta, M., Zhou, A., Webb, G., Carroll, R., Ravazzola, M., Orci, L., and Steiner, D.F. Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice. J. Biol. Chem. 276:27197-27202 (2001).  

Steiner, D.F. The prohormone convertases and precursor processing in protein biosynthesis. In: The Enzymes, Vol. XXII (eds. R.E. Dalbey and D.S. Sigman), pp. 163-198, Academic Press, New York, 2001. 

Ueda, K., Lipkind, G.M., Zhou, A., Zhu, X., Kuznetsov, A., Philipson, L., Gardner, P., Zhang, C., and Steiner, D.F. Mutational analysis of predicted interactions between the catalytic and P domains of prohormone convertase 3 (PC3/PC1). Proc. Natl. Acad. Sci. USA 100:5622-5627 (2003).