We are broadly interested in extracellular matrix (ECM) and its regulation by metalloproteases and their inhibitors. Our current focus is the ADAMTS superfamily of secreted proteins, which includes several ECM-modifying enzymes charged with critical functions in organogenesis, angiogenesis, and maturation of proproteins. Several ADAMTS proteases and the related ADAMTS-like proteins were discovered or first characterized by our laboratory. Our work is of a fundamental nature, utilizing developmental biology, genetics and protein chemistry and is relevant to arthritis, cancer, fibrosis and cardiovascular disorders. The current areas of emphasis are: 1. Developmental biology of ADAMTS proteases especially with regard to proteolysis of extracellular matrix (ECM) proteoglycans. 2. Regulation of TGF-beta activation by ECM. We study the role of ADAMTS10 and ADAMTSL2 vis-a-vis the matrix glycoprotein fibrillin-1, which has a critical role in TGF-beta activation. 3. Biochemistry of ADAMTS proteases and ADAMTS-like proteins: We analyze post-translational regulatory mechanisms, undertake structure-function analysis, and seek new substrates and interactions of these proteins.
Our body is made of living cells held together by a mortar or glue called extracellular matrix (ECM). ECM gives us a definite shape and form. It is also the means by which cells talk to each other, and it controls what cells do. Extracellular matrix is made of many molecules connected to each other to form networks and many of these have specialized functions. When ECM networks are disrupted, a variety of illnesses affecting organs such as the heart, bone, joints, eye and brain can result. Our body changes a lot over time, as we grow and age, and each time, it needs to be carefully broken down and rebuilt, just like remodeling a home. The mortar/ECM is broken down and rebuilt several times over our lifespan. Cells remodel their ECM using molecular tools called proteases that cut the extracellular matrix molecules in a well-controlled way. If this is uncontrolled, then there is destruction of tissues. This happens in arthritis and cancer. Our research group studies ECM and proteases and how they help to develop organs properly in the embryonic period. We also study happens when they don't work right, in conditions such as arthritis, cancer, heart disease and fibrosis.
Christine B. Kern, Medical University of South Carolina, SC
Robert Haltiwanger, Stony Brook University, NY
McCulloch, D.R., Nelson, C.M., Dixon, L.J., Silver D.L., Wylie, J.D., Lindner, V., Sasaki, T., Cooley, M.A., Argraves, W.S., Apte, S.S (2009). ADAMTS metalloproteases generate active versican fragments that regulate interdigital web regression. Dev Cell 17(5):687-98
Enomoto, H., Nelson, C., Somerville, R.P.T., Mielke, K., Dixon, L., Powell, K., Apte, S.S. (2010) Cooperation of two ADAMTS metalloproteases in closure of the mouse palate identifies a requirement for versican proteolysis in regulating palatal mesenchyme proliferation. Development, 37(23):4029-38.
W. E. Kutz, L. W. Wang, H. L. Bader, A. K. Majors,, K.Iwata, E. I. Traboulsi, L. Y. Sakai, D. R. Keene and S. S. Apte (2010). ADAMTS10 protein interacts with fibrillin-1 and promotes its deposition in extracellular matrix of cultured fibroblasts. J Biol Chem. 286, 17156-67
Lerner Research Institute
Mail Code NB21
9500 Euclid Avenue
Cleveland, Ohio 44195