Cell interactions with extracellular matrix control basic physiological processes, including development, response to injury, apoptosis, and pathological processes, such as fibrosis, arthritis and metastasis. Integrins are the major family of transmembrane receptors for extracellular matrix molecules. Syndecan-4 is a heparan sulfate proteoglycan that acts as a coreceptor with integrins for cell matrix adhesion, modifying the primary response. Signaling through syndecan-4 induces firm cell adhesion, and a lack of migration, through the formation of specialized adhesions, focal adhesions, that link to the cytoskeleton. The overall aim of this proposal is to determine how syndecan-4 nucleates and/or stabilizes adhesions. There are 3 specific aims, which will determine: 1) whether syndecan-4 association with protein kinase C-alpha, alpha-actinin or integrins nucleates of stabilizes adhesions. This will involve localization, coprecipitation and transfection experiments, and identification of interaction sites; 2) how downstream signaling via PKC-alpha controls adhesion formation and stability. This will involve in vitro phosphorylation assays and analysis of phosphorylation of cellular components before and after syndecan-4 ligation; and 3) how oligomerization of syndecan-4 is controlled. Syndecan-4 must oligomerize for activity, but control of oligomerization has not been systematically studied. Chimeric and mutated syndecans will be used in both in vitro and in situ assays to determine oligomerization sites. Results from these studies will identify targets for regulating syndecan-4 interactions with both intracellular and extracellular binding partners crucial for the formation and/or stabilization of stable adhesions. The goal is to identify new avenues for future interventional therapies to control adhesion phenotype that are more specific than at present.
| Thodeti, Charles Kumar; Albrechtsen, Reidar; Grauslund, Morten et al. (2003) ADAM12/syndecan-4 signaling promotes beta 1 integrin-dependent cell spreading through protein kinase Calpha and RhoA. J Biol Chem 278:9576-84 |
| Couchman, John R; Vogt, Susan; Lim, Ssang-Taek et al. (2002) Regulation of inositol phospholipid binding and signaling through syndecan-4. J Biol Chem 277:49296-303 |
