Extracellular Matrix Pathology
William G. Stetler-Stevenson, MD, PhD., Head, Extracellular Matrix Pathology Section
Building 10, Room 6B05
Extracellular Matrix Pathology Section
Laboratory of Pathology, CCR
National Cancer Institute
Building 10, Room 6B01
10 Center Dr.
Bethesda, MD 20892-1500
The Extracellular Matrix (ECM) Pathology Section investigates novel biologic functions of matrix molecules in regulation/modulation of tissue homeostasis, cellular invasion and migration. Specifically, we are focused on the role of Matrix Metalloproteinases (MMPs) and their endogenous inhibitors. Early work in our laboratory identified the molecular and cellular mechanisms of MMP2 activation, and discovery of a new member of the Tissue Inhibitor of MetalloProteinase family, TIMP-2 1-3.
The overarching principle of our research is to utilize highly focused, multifaceted approaches to rigorously study the mechanisms of ECM composition, function and structure in suppression of cell growth, migration, invasion and angiogenesis. Disruption of these pathways contributes to the pathogenesis of chronic diseases, such as cancer progression and metastasis, as well as cardiovascular and neurodegenerative diseases. Our working premise that TIMPs are multifunctional proteins, not just protease inhibitors, was based on our observations that TIMP2 suppression of cell proliferation is dissociable from the MMP inhibitory activity 4,5 (See Figure 1). Continuing investigation led my laboratory to develop a novel TIMP-2 reagent lacking MMP inhibitory activity know as Ala+TIMP-2 6. Utilizing this novel reagent we successfully demonstrate that TIMP-2 inhibition of angiogenesis and primary tumor growth are mediated via MMP-independent mechanism requiring cell surface integrin receptor interactions and protein phosphatase activity 7-10. Our current objective is to translate these basic discoveries of TIMP biology into new effective treatment strategies to prevent disease progression that will result in substantial clinical therapeutic and public health impact.
Ongoing research efforts are directed at elucidating the functional significance of recently discovered post-translational modifications (phosphorylation)11, and co-chaperone role of TIMP2 in regulation of MMP2 activity and cellular functions described above12.
1 Stetler-Stevenson, W. G., Brown, P. D., Onisto, M., Levy, A. T. & Liotta, L. A. Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. J Biol Chem 265, 13933-13938 (1990).
2 Stetler-Stevenson, W. G., Krutzsch, H. C. & Liotta, L. A. TIMP-2: identification and characterization of a new member of the metalloproteinase inhibitor family. Matrix Suppl 1, 299-306 (1992).
3 Stetler-Stevenson, W. G., Krutzsch, H. C., Wacher, M. P., Margulies, I. M. & Liotta, L. A. The activation of human type IV collagenase proenzyme. Sequence identification of the major conversion product following organomercurial activation. J Biol Chem 264, 1353-1356 (1989).
4 Hoegy, S. E., Oh, H. R., Corcoran, M. L. & Stetler-Stevenson, W. G. Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) Suppresses TKR-Growth Factor Signaling Independent of Metalloproteinase Inhibition. J Biol Chem 276, 3203-3214, doi:10.1074/jbc.M008157200 (2001).
5 Murphy, A., Unsworth, E. J. & Stetler-Stevenson, W. G. Tissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferation. Journal of Cellular Physiology 157, 351-358, doi:10.1002/jcp.1041570219 (1993).
6 Wingfield, P. T. et al. Biophysical and functional characterization of full-length, recombinant human tissue inhibitor of metalloproteinases-2 (TIMP-2) produced in Escherichia coli. Comparison of wild type and amino-terminal alanine appended variant with implications for the mechanism of TIMP functions. J Biol Chem 274, 21362-21368, doi:10.1074/jbc.274.30.21362 (1999).
7 Bourboulia, D. et al. TIMP-2 modulates cancer cell transcriptional profile and enhances E-cadherin/beta-catenin complex expression in A549 lung cancer cells. Oncotarget 4, 163-173 (2013).
8 Bourboulia, D. et al. Endogenous angiogenesis inhibitor blocks tumor growth via direct and indirect effects on tumor microenvironment. Am J Pathol 179, 2589-2600, doi:10.1016/j.ajpath.2011.07.035 (2011).
9 Seo, D.-W. et al. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 114, 171-180 (2003).
10 Seo, D. W. et al. Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in human microvascular endothelial cells. J Biol Chem 281, 3711-3721, doi:10.1074/jbc.M509932200 (2006).
11 Sànchez-Pozo, J. et al. Extracellular Phophorylation of TIMP-2 by Secreted c-Src Tyrosing Kinase Controls MMP-2 Activity. iScience 1, 87-96 (2018).
12 Baker-Williams, A. J. et al. Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis. Cell Rep 28, 1894-1906 e1896, doi:10.1016/j.celrep.2019.07.045 (2019).