Daniel J. Knauer

Picture of Daniel J. Knauer
Professor, Developmental & Cell Biology
School of Biological Sciences
PH.D., University of Nebraska, 1979
Phone: (949) 824-5357, 4703
Fax: (949) 824-4709
Email: djknauer@uci.edu
University of California, Irvine
5232, 5415 McGaugh Hall
Mail Code: 2300
Irvine, CA 92697
Research Interests
Serine protease regulation at the cell-surface
Research Abstract
The research in my laboratory focuses on the structure and function the super-gene family of SERine Protease INhibitors (SERPINs) and the receptors which mediate clearance of these proteins when they are in complex with proteases. Members of the SERPIN gene family regulate several biological processes including cell division and migration, neurite extension, tumor cell metastasis, and blood coagulation. The SERPINS act as specific inhibitors of cell-surface and extracellular matrix serine proteases that participate in cascade mechanisms that participate in these biological processes. A unique feature of the SERPINS is the up-regulation of their antiprotease activity by specific glycosaminoglycans (such as heparin) found in the extra-cellular matrix and in soluble forms. This activation, which is on the order of 10,000-fold, is mediated by a conformational change in the SERPIN induced by the binding of the glycosaminoglycan to a specific domain within the protein.

Several areas of research, including SERPIN:Protease complex metabolism, lipid metabolism, and Alzheimer’s Disease have recently converged because all involve interactions with one receptor: the low density lipoprotein-receptor-related protein(LRP). The LRP is unusual in that it mediates the internalization of a large array of ligands, some of which appear to be only distantly related. The majority of the ligands that utilize the LRP for endocytosis first interact with cells via a heparin binding site, and remain there until they are triggered to endocytose via the LRP. At least one other well characterized cell surface receptor is used as a co-receptor for the LRP; the urinary plasminogen activator receptor (uPAR). Localization of uPA to the cell-surface by the uPAR is a key mechanism that allows for carefully localized proteolysis of matrix components in the process of cell migration. This places the LRP in an important regulatory role, since it is the vehicle that removes ligands from the cell surface, and in effect regulates ligand distribution and alters cell-environmental interactions.

My laboratory utilizes SERPIN:protease complex metabolism as a model system to probe several larger basic questions in cell biology. It is now widely recognized that the use of heparin and other cell-surface molecules as co-receptors is more ubiquitous than previously recognized. Part of our studies are aimed at elucidating the role(s) of cell surface heparin sulfate proteolycans (HSPG’s) both as co-receptors that deliver ligands to the LRP, and as post-endocytic sorting vehicles. A large effort is also devoted to identifying the structural domains in the LRP that mediate the internalization of specific ligands, since this is a first step toward manipulating the LRP at the pharmacological level. Our very interesting and recent observation that PN1 is a potent inhibitor of Factor XIa, in the blood coagulation cascade, places PN1 as a potential key regulatory element in this cascade as well as in the pathology of Alzheimer’s disease.
Knauer, M.F., Hawley,S.B. & D.J. Knauer (1997) Identification of a binding site in human protease nexin 1 required for the receptor mediated internalization of PN1-thrombin complexes. J.Biol.Chem.272:12261-4.
Knauer, M.F., Kridel, S.J., Hawley, S.B. and D.J. Knauer (1997) The efficient catabolism of thrombin:protease nexin 1 complexes is a synergistic mechanism that requires both the LDL receptor-related protein and cell-surface heparins. J. Biol. Chem. 272: 29039-45.
Knauer, M.F., Crisp, R. J., Kridel, S.J., and Knauer, D.J. (1999) Analysis of a structural determinant in thrombin-protease nexin 1 complexes which mediates clearance by the LDL receptor-related protein. J. Biol. Chem., 274: 275-81.
Crisp, R. J., Knauer, D. J. and Knauer, M.F., (2000) The heparin binding site in protease nexin 1 is required for the retention and degradation, but not the binding or internalization of urokinase: protease nexin 1 complexes. J. Biol. Chem. 275:19628-37.
Knauer, D.J., Majumdar, D. Fong, P. & Knauer, M.F. (2000) SERPIN regulation of factor XIa: The novel observation that PN1 inhibits factor XIa ten times faster than C1 inhibitor in the presence of heparin. J. Biol. Chem., Papers in Press.
Graduate Programs
Cell Biology
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