Nancy M. Dahms, Ph.D.
Professor
Dr. Dahms received her Bachelor of Science degree from Marquette University in 1980 and her Doctorate degree in Biochemistry from the Johns Hopkins University School of Medicine in 1986. She was a postdoctoral fellow at Washington University School of Medicine from 1986-1989 where she isolated and characterized the cDNA clones for the receptors involved in targeting lysosomal enzymes to the lysosome. She joined the faculty of the Medical College of Wisconsin in 1989.
Contact Information
ndahms@mcw.edu
Phone: (414) 456-4698
Fax: (414) 456-6510
Research Interests
Our research investigates the molecular mechanisms underlying the functioning of mannose 6-phosphate receptors (MPRs) in mammalian cells. Two areas of research are currently in progress:
1. Lysosome Biogenesis: A fundamental question in biochemistry today is how various proteins are targeted to their proper intracellular location. The targeting of lysosomal enzymes to lysosomes, which involves carbohydrate signals and receptors, is one of the best characterized systems for addressing this question. The transport of newly synthesized lysosomal enzymes to the lysosome in mammalian cells is dependent upon MPRs. Two distinct but homologous receptors, the 300kDa insulin-like growth factor II/cation-independent MPR (IGF-II/CI-MPR) and the 46kDa cation-dependent MPR (CD-MPR), have been identified.
In order to determine the 3-dimensional structure of the receptors, crystallographic studies are currently underway in collaboration with Dr. Jung-Ja Kim. These studies have led to a high resolution structure (1.8Å) of the extracytoplasmic domain of the CD-MPR and the N-terminal region (domains1-3) of the IGF-II/CI-MPR in the presence of bound mannose 6-phosphate. In collaborative studies with Dr. Brian Volkman, NMR spectrosopy is being used to evaluate the dynamics of CD-MPR movement as a function of ligand binding and pH.
2. Regulation of Signaling Pathways and Growth Factor Activity: The IGF-II/CI-MPR is a multifunctional protein that binds mannose 6-phosphate on lysosomal enzymes, insulin-like growth factor II (IGF-II; a mitogenic growth factor that is essential for normal fetal growth and is overexpressed in many cancers), retinoic acid, plasminogen, and urokinase-type plasminogen activator receptor (uPAR). The receptor controls the availability of IGF-II to signal through the IGF-I/insulin receptor by targeting this mitogenic growth factor for degradation in the lysosome. The IGF-II/CI-MPR has been shown to function in vivo as a tumor suppressor gene in several animal model systems by its ability to regulate the levels of IGF-II. In addition, the IGF-II/CI-MPR has been shown to participate in activating transforming growth factor-β (TGF-β) at the cell surface. To better understand at the molecular level how the IGF-II/CI-MPR functions to bind such a diversity of ligands, we are utilizing molecular, cellular and biophysical approaches to identify residues essential for ligand binding and ultimately regulating signaling pathways.
3. Insulin-Like Growth Factor II and Mannose 6-Phosphate Receptors in Polarized Epithelial Cells: We are examining the factors which regulate the expression and cellular sorting of the MPRs and their ligands in polarized intestinal epithelial cells during development and cellular differentiation. Enterocytes are rapidly proliferating cells of the intestinal mucosa which perform important functions in nutrient and ion transport. An in vitro cell culture system using Caco-2 cells is being used to address the role MPRs, lysosomal enzymes, IGF-II, and IGF binding proteins have in the normal growth, differentiation, and function of enterocytes. In addition, we are analyzing the mechanisms by which the MPRs are expressed in a polarized fashion on the cell surface of Caco-2 cells.
Linda Olson, Ph.D., a Research Scientist in the laboratory, is currently working on the generation of diffraction-quality crystals of the MPRs and on the identification of residues involved in ligand binding.
Alicia Castonguay is a graduate student who is studying the regulation of signaling pathways by the MPRs.
Selected Publications
"Structural Insights into the mechanism of pH-dependent ligand binding and release by the cation-dependent mannose 6-phosphate receptor." L.J. Olson, O. Hindsgaul, N.M. Dahms and J.-J. P. Kim J. Biol. Chem. 283: 10124-10134 (2008)
"Domain 5 of the Cation-Independent Mannose 6-Phosphate Receptor Preferentially Binds Phosphodiesters (Mannose 6-Phosphate N-Acetylglucosamine Ester)." C.A. Chavez, R.N. Bohnsack, M. Kudo, R.R. Gotschall, W.M. Canfield, and N.M. Dahms Biochemistry 46:12604-12617 (2007)
"Identification of Residues Essential for Carbohydrate Recognition and Cation Dependence of the 46kDa Mannose 6-Phosphate Receptor." G. Sun, H. Zhao, B. Kalyanaraman, N.M. Dahms Glycobiology 15: 1136-1149 (2005).
"Identification of a Low-Affinity Mannose 6-Phosphate Binding Site in Domain 5 of the Cation-Independent Mannose 6-Phosphate Receptor." S. T. Reddy, W. Chai, R. A. Childs, J. D. Page, T. Feizi, and N. M. Dahms J. Biol. Chem. 279: 38658-38667 (2004).
"The N-Terminal Carbohydrate Recognition Site of the Cation-Independent Mannose 6-Phosphate Receptor." L. J. Olson, N. M. Dahms, and J.-J. P. Kim. J. Biol. Chem. 279: 34000-34009 (2004).
"Structure of the uPAR, Plasminogen, and Sugar Binding Sites of the 300 kDa Mannose 6-Phosphate Receptor." L. J. Olson, R. Yammani, N. M. Dahms, and J.-J. P. Kim EMBO J 23: 2019-2028 (2004).
"Mannose 6-Phosphate Receptors: New Twists in the Tale." P. Ghosh, N.M. Dahms and S. Kornfeld Nature Rev. Mol. Cell Biol. 4: 202-212 (2003).
"P-Type Lectins." N.M. Dahms and M.K. Hancock Biochem. Biophys. Acta 1572: 317-340 (2002).
"Localization of the Carbohydrate Recognition Sites of the Insulin-Like Growth Factor II/Mannose 6-Phosphate Receptor to Domains 3 and 9 of the Extracytoplasmic Region." M.K. Hancock, R.D. Yammani, N.M. DahmsJ. Biol. Chem. 277: 47205-47212 (2002).
"Identification of Residues Essential for Carbohydrate Recognition by the Insulin-Like Growth Factor II/Mannose 6-Phosphate Receptor." M. K. Hancock, D. J. Haskins, G. Sun, and N. M. Dahms J. Biol. Chem. 277: 11255-11264 (2002).
"Twists and Turns of the Cation-Dependent-Mannose 6-Phosphate Receptor: Ligand-Bound versus Ligand-Free Receptor." L. J. Olson, J. Zhang, N. M. Dahms, and J.-J. P. Kim J. Biol. Chem. 277: 10156-10161 (2002).
"The Basolateral Sorting Signal of the 300kDa Mannose 6-Phosphate Receptor." D. A. Wick, B. Seetharam, and N. M. Dahms Am. J. Physiol. 282, G51-G60 (2002).
"Recognition of Dictyostelium discoideum Lysosomal Enzymes is Conferred by the Amino-Terminal Carbohydrate Binding Site of the Insulin-Like Growth Factor II/Mannose 6-Phosphate Receptor." P. G. Marron-Terada, M. K. Hancock, D. J. Haskins, and N. M. Dahms Biochemistry 39: 2243-2253 (2000).
"Mutational Analysis of the Binding Site Residues of the Bovine Cation-Dependent Mannose 6-Phosphate Receptor." L. J. Olson, M. K.Hancock, D. Dix, J.-J. P. Kim, and N. M. Dahms J. Biol. Chem. 274: 36905-36911(1999).
"Structural Basis for Recognition of Phosphorylated High Mannose Oligosaccharides by the Cation-Dependent Mannose 6-Phosphate Receptor." L. J. Olson, J. Zhang, Y. C. Lee, N. M. Dahms, and J.-J. P. Kim J.Biol. Chem. 274: 29889-29896 (1999).
"Biosynthesis and Secretion of the Mannose 6-Phosphate Receptor and Its Ligands in Polarized Caco-2 Cells." D. A. Wick, B. Seetharam,and N. M. Dahms Am. J. Physiol. 277: G506-G514 (1999).
"Characterization of Truncated and Glycosylation-Deficient Forms of the Cation-Dependent Mannose 6-Phosphate Receptor Expressed in Baculovirus-Infected Insect Cells." P.G. Marron-Terada, K.E. Bollinger,and N. M. Dahms. Biochemistry 37: 17223-17229 (1998).
"Molecular Basis of Lysosomal Enzyme Recognition: Three-Dimensional Structure of the Cation-Dependent Mannose 6-Phosphate Receptor." D.L.Roberts, D.J. Weix, N.M. Dahms, and J.-J.P. Kim. Cell 93: 639-648 (1998).
"The Two Mannose 6-Phosphate Binding Sites of the Insulin-like Growth Factor-II/Mannose 6-Phosphate Receptor Display Different Ligand Binding Properties." P. G. Marron-Terada, M.A. Brzycki-Wessell, and N.M. Dahms. J. Biol. Chem. 273: 22358-22366 (1998).