Interactions of cells with the extracellular matrix are critically important events in normal tissue organization, repair and remodeling. Such interactions are generally considered to be mediated by multiple mechanisms. We will continue our studies demonstrating that receptor molecules embedded in the plasma membrane are involved in interacting with fibronectin outside the cell and microfilaments inside the cell. These molecules are expected to undergo modulation in quantity or position at the cell surface during expression of specialized cell functions. Our goals are to characterize these cell surface moleucles, to define their functional roles and cell biological properties in their interactions with the matrix, and to examine in vivo whether modulation of these cell surface molecules plays a particularly important regulative role in lung cell function by anchoring cells to the matrix, controlling cell migration and phagocytosis, and altering cytoskeletal organization and function. Specifically, (1) monoclonal and polyclonal antibodies directed against a putative fibronectin receptor (the 140K complex), and its copurified subunit polypeptides will continue to be generated. These antibodies, in conjunction with affinity purification, electron microscopy, and limited proteolysis will provide the basis for facile isolation and analysis of active domains of the 140K polypeptides and of their interactions with the matrix. (2) We will use a combined morphological and biochemical assay to examine extracellular fibroenctin-degrading activities of normal tissue cells, and their involvement in lung cell migration and phagocytosis. When the proteases are identified, their functional relationships with the 140K polypeptides in these cells will also be examined. (3) We will extend the recently developed technology of ultrathin-frozen-sectioning of lung tissues, and in conjunction with microinjection and labeling by monoclonal antibodies or other ligands, examine the expression of these cell surface molecules and their interactions with cytoskeletal and matrix components in normal and diseased lungs. Similar to in vitro studies using isolated cells, we will also look for the binding of exogeneous fibronectin to cells in situ and its subsequent degradation within lung tissue sections.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Georgetown University
Schools of Medicine
United States
Zip Code
Chen, Wen-Tien; Kelly, Thomas (2003) Seprase complexes in cellular invasiveness. Cancer Metastasis Rev 22:259-69
Chen, Wen-Tien; Kelly, Thomas; Ghersi, Giulio (2003) DPPIV, seprase, and related serine peptidases in multiple cellular functions. Curr Top Dev Biol 54:207-32
Artym, Vira V; Kindzelskii, Andrei L; Chen, Wen-Tien et al. (2002) Molecular proximity of seprase and the urokinase-type plasminogen activator receptor on malignant melanoma cell membranes: dependence on beta1 integrins and the cytoskeleton. Carcinogenesis 23:1593-601
Ghersi, Giulio; Dong, Huan; Goldstein, Leslie A et al. (2002) Regulation of fibroblast migration on collagenous matrix by a cell surface peptidase complex. J Biol Chem 277:29231-41
Ghersi, G; Chen, W; Lee, E W et al. (2001) Critical role of dipeptidyl peptidase IV in neuropeptide Y-mediated endothelial cell migration in response to wounding. Peptides 22:453-8
Nakahara, H; Mueller, S C; Nomizu, M et al. (1998) Activation of beta1 integrin signaling stimulates tyrosine phosphorylation of p190RhoGAP and membrane-protrusive activities at invadopodia. J Biol Chem 273:9-12
Goldstein, L A; Ghersi, G; Pineiro-Sanchez, M L et al. (1997) Molecular cloning of seprase: a serine integral membrane protease from human melanoma. Biochim Biophys Acta 1361:11-9
Pineiro-Sanchez, M L; Goldstein, L A; Dodt, J et al. (1997) Identification of the 170-kDa melanoma membrane-bound gelatinase (seprase) as a serine integral membrane protease. J Biol Chem 272:7595-601
Nakahara, H; Howard, L; Thompson, E W et al. (1997) Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cell invasion. Proc Natl Acad Sci U S A 94:7959-64
Kelly, T; Mueller, S C; Yeh, Y et al. (1994) Invadopodia promote proteolysis of a wide variety of extracellular matrix proteins. J Cell Physiol 158:299-308

Showing the most recent 10 out of 25 publications