The cell adhesive glycoprotein fibronectin (FN) is deposited in specific pathways during embryogenesis that are followed by migrating cells, and as part of the extracellular matrix in most organs. Blocking the interaction of embryonic cells with FN causes profound disturbances in development. In adults, circulating plasma FN is synthesized by the liver, but little appears to be synthesized in other tissues. However, during wound repair FN expression is coordinately increased along with other connective tissue components, possibly as a result of polypeptide growth factors such as transforming growth factor beta that stimulate FN and FN receptor expression and that also act during embryogenesis. Cells transformed with oncogenic viruses typically lose their FN matrices, and this disturbance in cell-matrix interaction may be responsible for some abnormalities of the transformed phenotype, including even metastasis. Cells interact with FN-containing matrices via specific transmembrane receptors in the VLA subfamily of integrins. However, we have shown that the deposition of FN matrices requires the specific binding of cells to an aminoterminal site in FN distinct that interacting with adhesive cellular receptors. Thus, two separate systems of cellular interactions with FN exist, one for deposition and the other for recognition. Because FN-containing matrices appear to play such a vital role in growth, development, wound healing and possible tumor metastasis, it is important to understand how they are deposited. To do this, we plan to: 1) Isolate and characterize the cell surface molecules interacting with FN's aminoterminal 29 kDa matrix assembly domain. 2) Study structure-function relationships in the aminoterminal matrix assembly domain using recombinant DNA. 3) Elucidate the role of FN's matrix assembly and cell adhesive domains in binding to cells, and determine if deficient binding of FN's aminoterminal matrix assembly domain accompanies oncogenic transformation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM038276-06
Application #
3294540
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1986-08-01
Project End
1991-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wu, C; Chung, A E; McDonald, J A (1995) A novel role for alpha 3 beta 1 integrins in extracellular matrix assembly. J Cell Sci 108 ( Pt 6):2511-23
Simon, E E; Liu, C H; Das, M et al. (1994) Characterization of integrins in cultured human renal cortical tubule epithelial cells. Am J Physiol 267:F612-23
Roman, J; McDonald, J A (1993) Fibulin's organization into the extracellular matrix of fetal lung fibroblasts is dependent on fibronectin matrix assembly. Am J Respir Cell Mol Biol 8:538-45
Wu, C; Bauer, J S; Juliano, R L et al. (1993) The alpha 5 beta 1 integrin fibronectin receptor, but not the alpha 5 cytoplasmic domain, functions in an early and essential step in fibronectin matrix assembly. J Biol Chem 268:21883-8
McDonald, J A (1991) Idiopathic pulmonary fibrosis. A paradigm for lung injury and repair. Chest 99:87S-93S
McDonald, J A (1991) Applications of cell and molecular biology to pneumonology. Schweiz Med Wochenschr 121:89-95
Limper, A H; Quade, B J; LaChance, R M et al. (1991) Cell surface molecules that bind fibronectin's matrix assembly domain. J Biol Chem 266:9697-702
Simon, E E; McDonald, J A (1990) Extracellular matrix receptors in the kidney cortex. Am J Physiol 259:F783-92
Roman, J; LaChance, R M; Broekelmann, T J et al. (1989) The fibronectin receptor is organized by extracellular matrix fibronectin: implications for oncogenic transformation and for cell recognition of fibronectin matrices. J Cell Biol 108:2529-43
McDonald, J A (1989) Receptors for extracellular matrix components. Am J Physiol 257:L331-7

Showing the most recent 10 out of 15 publications