Matrix metalloproteinases (MMPs) secreted by eucaryotic cells initiate tissue remodeling by degradation of existing extracellular matrix (ECM) macromolecules such as collagens and proteoglycans.
In the laboratory of Dr. Gregory Goldberg, (Department of Internal Medicine/Dermatology and Biochemistry and Molecular Biophysics) the biological function of these proteinases and their role in connective tissue turnover is investigated, specifically their interaction with fixed molecular structures on the cell surfaces and/or fibrils of the ECM.
Membrane-bound enzymes of these proteinases are involved in proteolytic activation of Gelatinase A (GelA), with other functions yet to be discovered. Malignant cells exploit these proteinases to promote tumor invasion and metastasis.
Our research into biological function of MMPs is based on the hypothesis that spatially regulated extracellular proteolysis is accomplished by compartmentalization of the enzymes via their interaction with molecular structures on the cell surfaces and/or fibrils of the ECM where the physiological activation of proenzymes occurs.
Thus, mechanistic study of such interactions is a major focus of our attention. In this respect, the discovery of a cell surface activation mechanism of GelA and isolation of its membrane activator were recent breakthroughs. The regulatory C-terminal domain of GelA (GelACTD) plays a pivotal role in activation mechanism and substrate recognition. We recently have reported the crystal structure of this domain. Now, based on this structure, we have created and characterized a library of 60 single amino-acid substitution mutants that span solvent-exposed residues of this domain. These mutants will be instrumental in further investigation of the enzyme activation mechanisms. We combine biochemical, biophysical and molecular biology approaches to study the mechanisms of extracellular proteolysis by secreted and membrane-bound metalloproteinases to understand the role of these enzymes in cell motility and invasion.
Within the division, the study of matrix metalloproteinases has been a historical strength.
Dr. Eugene Bauer was the first trainee and post-doctoral fellow under the direction of Dr. A. Eisen. Dr. Bauer developed an independent research career in matrix biology within the Division, successfully mentoring his own trainees with the support of the program. Dr. Bauer departed Washington University in 1988 to become Chair of the Department of Dermatology, and ultimately the Dean of Stanford Medical School.
A second early trainee, Dr. Jouni Uitto, a resident and post-doctoral fellow with Dr. Eisen, also began his investigative career in matrix biology within the Division and continues to be an internationally known researcher in the genetics of connective tissue diseases of the skin. He is presently Chairman of the Department of Dermatology at Jefferson Medical College in Philadelphia.