Extracellular matrix (ECM) remodeling plays a critical role in tissue reorganization. Understanding mechanisms that regulate ECM proteolysis during tumor development and angiogenesis is of paramount importance to the treatment of malignancies. Our studies will provide valuable information about mechanisms which control ECM proteolysis. Our hypothesis is that specific interactions of MMPs with molecular receptors on the cell surface govern ECM remodeling involved in tumor growth and angiogenesis. Our data suggest that MT1-MMP, TIMP-2, and alphavbeta3 integrin jointly control the activation and docking of secretory MMP-2. MT1-MMP initiates activation of MMP-2 and alphavbeta3 facilitates autocatalytic maturation of MMP-2. Furthermore, MT1-MMP mediates generation of the modified beta3 integrin subunit which correlates with increased migration of tumor cells. A disulfide bridge with an intracellular, presumably cytoskeletal, protein can direct MT1-MMP to discrete regions on the cell surface in an immediate proximity to alphavbeta3. The identified mechanisms could be a link in joining continually changing cell shape, cytoskeleton, and focal proteolysis of the ECM. According to our model, docking of MMP-2 co-exists with its activation at the cell surface, thereby illustrating how latent MMP-2 produced by the stroma could be specifically localized at tumor cells as the mature enzyme. We suggest that these are basic mechanisms employed not only by tumor cells, but also by endothelial cells to spatially and temporally control ECM proteolysis during tumor development.
Our aims are: 1) To enzymologically characterize MT1-MMP and to complete the characterization of the MMP-2 activation cascade. 2) To functionally and structurally characterize a novel species of the beta3 integrin subunit. 3) To establish specific roles of MT1-MMP, MMP-2, and alphavbeta3 in tumor angiogenesis and to identify novel targets for inhibition of tumor neovascularization. 4) To generate novel angiogenic inhibitors derived from critical functional and structural elements of the C-terminal domains of MMP-2 and MT1-MMP. We anticipate our studies will lead to novel methods of cancer therapy based on the modulation of ECM remodeling and inhibition of tumor angiogenesis.
|Cieplak, Piotr; Strongin, Alex Y (2017) Matrix metalloproteinases - From the cleavage data to the prediction tools and beyond. Biochim Biophys Acta Mol Cell Res 1864:1952-1963|
|Remacle, Albert G; Cieplak, Piotr; Nam, Dong Hyun et al. (2017) Selective function-blocking monoclonal human antibody highlights the important role of membrane type-1 matrix metalloproteinase (MT1-MMP) in metastasis. Oncotarget 8:2781-2799|
|Chernov, Andrei V; Reyes, Leticia; Peterson, Scott et al. (2015) Depletion of CG-Specific Methylation in Mycoplasma hyorhinis Genomic DNA after Host Cell Invasion. PLoS One 10:e0142529|
|Chernov, Andrei V; Reyes, Leticia; Xu, Zhenkang et al. (2015) Mycoplasma CG- and GATC-specific DNA methyltransferases selectively and efficiently methylate the host genome and alter the epigenetic landscape in human cells. Epigenetics 10:303-18|
|Kukreja, Muskan; Shiryaev, Sergey A; Cieplak, Piotr et al. (2015) High-Throughput Multiplexed Peptide-Centric Profiling Illustrates Both Substrate Cleavage Redundancy and Specificity in the MMP Family. Chem Biol 22:1122-33|
|Alonso, Sergio; Dai, Yuichi; Yamashita, Kentaro et al. (2015) Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans. Oncotarget 6:3420-31|
|Golubkov, Vladislav S; Strongin, Alex Y (2014) Downstream signaling and genome-wide regulatory effects of PTK7 pseudokinase and its proteolytic fragments in cancer cells. Cell Commun Signal 12:15|
|Shiryaev, Sergey A; Aleshin, Alexander E; Muranaka, Norihito et al. (2014) Structural and functional diversity of metalloproteinases encoded by the Bacteroides fragilis pathogenicity island. FEBS J 281:2487-502|
|Ratnikov, Boris I; Cieplak, Piotr; Gramatikoff, Kosi et al. (2014) Basis for substrate recognition and distinction by matrix metalloproteinases. Proc Natl Acad Sci U S A 111:E4148-55|
|Remacle, Albert G; Shiryaev, Sergey A; Strongin, Alex Y (2014) Distinct interactions with cellular E-cadherin of the two virulent metalloproteinases encoded by a Bacteroides fragilis pathogenicity island. PLoS One 9:e113896|
Showing the most recent 10 out of 90 publications