Several mechanochemical processes coordinated at the cell surface are essential for normal tissue formation and integrity. A guiding theme for our work continues to be the idea that the primary processes of cell migration, cell proliferation and cell adhesion regulate and are regulated by the cross-linkage of cell surface glycoproteins and their interactions with the cytoskeleton (global modulation), and are influenced by changes in the amount, distribution and properties of specific cell surface receptors (local modulation). To corroborate this hypothesis and to examine the role of proteins involved in tissue formation in the control of primary processes, we have isolated and characterized three cell adhesion molecules (N-CAM, L-CAM, and Ng-CAM) and have recently discovered a novel extracellular matrix (ECM) protein (cytotacin) that is involved in both cell-matrix adhesion and cell migration. The distributions of each of these molecules show dynamic alterations during development that are consistent with their identified functions. Furthermore, expression of the CAMs and cytotactin is altered in transformed cells, raising the possibility that alterations in the expression of these molecules is a crucial correlate of the transformed phenotype. We now propose to extend and deepen our study of the dynamics of cell surface modulation. Specifically, we will: 1) determine the structural features of cytotactin at both the protein and nucleic acid levels, with particular regard to known features of CAMs and extracellular matrix proteins; 2) carry out functional assays to describe the role of cytotactin in cell movement and search for its cellular receptors; 3) use monoclonal antibodies to a carbohydrate antigen (NC-1/HNK-1) present on cytotactin, N-CAM, and Ng-CAM to identify other cell surface and ECM proteins that might be involved in adhesion; 4) relate local cell surface modulation to global modulation in nerve-muscle and hepatocyte interactions and determine whether ECM proteins can induce global modulation; and 5) determine whether the effects of viral transformation consistently correlate with modulation of molecules that mediate cell-cell and cell-substrate interactions in neural and epithelial cells. The results of these studies should provide valuable clues to the regulation of fundamental cellular processes, and may be of significant value to our understanding of a variety of disease states including birth defects, tissue disorders, cancer and metastasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK004256-34
Application #
3482875
Study Section
Special Emphasis Panel (NSS)
Project Start
1976-09-01
Project End
1994-08-31
Budget Start
1992-09-07
Budget End
1993-08-31
Support Year
34
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Copertino, D W; Jenkinson, S; Jones, F S et al. (1995) Structural and functional similarities between the promoters for mouse tenascin and chicken cytotactin. Proc Natl Acad Sci U S A 92:2131-5
Phillips, G R; Edelman, G M; Crossin, K L (1995) Separate cell binding sites within cytotactin/tenascin differentially promote neurite outgrowth. Cell Adhes Commun 3:257-71
Edelman, G M (1994) Adhesion and counteradhesion: morphogenetic functions of the cell surface. Prog Brain Res 101:1-14
Krushel, L A; Prieto, A L; Edelman, G M et al. (1994) Differential effects of cytotactin/tenascin fusion proteins on intracellular pH and cell morphology. J Cell Physiol 161:508-18
Prieto, A L; Edelman, G M; Crossin, K L (1993) Multiple integrins mediate cell attachment to cytotactin/tenascin. Proc Natl Acad Sci U S A 90:10154-8
Edelman, G M (1993) A golden age for adhesion. Cell Adhes Commun 1:1-7
Grumet, M; Friedlander, D R; Edelman, G M (1993) Evidence for the binding of Ng-CAM to laminin. Cell Adhes Commun 1:177-90
Jones, F S; Holst, B D; Minowa, O et al. (1993) Binding and transcriptional activation of the promoter for the neural cell adhesion molecule by HoxC6 (Hox-3.3). Proc Natl Acad Sci U S A 90:6557-61
Edelman, G M; Jones, F S (1993) Outside and downstream of the homeobox. J Biol Chem 268:20683-6
Prieto, A L; Andersson-Fisone, C; Crossin, K L (1992) Characterization of multiple adhesive and counteradhesive domains in the extracellular matrix protein cytotactin. J Cell Biol 119:663-78

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