Fibronectin mediated cell migration: signal integration

State University New York Stony Brook, Stony Brook NY

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Abstract

DESCRIPTION (Taken from the applicant's abstract): The candidate has a M.D. and a Ph.D. degree, and was recently appointed Assistant Professor of Research, Dermatology. The candidate is commiitted to biomedical research related to the wound healing process. The candidate's long term goal is to independently direct biomedical research in an academic setting. Fibronectin (FN) is critical for wound healing largely by promoting mesenchymal cell migration into the wound. Several domains of FN interact with their respective cell receptors that include integrins and non-integrin receptors such as syndecan-4. The interaction of FN central cell binding domain with alpha5beta integrin mediates most of FNs cell adhesion activity. However, data indicate that efficient migration of dermal fibroblasts over FN requires additional domains, namely the major heparin-binding (Hep-II) domain and the IIICS domain. How these domains cooperate to achieve maximal cell migration is not clear. The goal of this study is to understand the effect of FN domains on cell motility by studying the underlying signal-transduction pathways and their integration. The Rho family of small GTPases plays an important role in regulating cell migration. Preliminary data indicate that the cell-binding domain and the heparin-binding domain of FN have opposing effect on Rho activity, indicating the two domains converge their signals at the level of Rho activity. Interaction of FNs cell-binding domain with integrins activates focal adhesion kinase (FAK), which facilitates focal adhesion turnover and cell migration via inhibition of Rho. Strong inhibition of Rho, however, impairs cell migration as Rho-generated contractile force is required for migration. Elevation of Rho activity by the heparin-binding domain of FN leads to a dynamic balance of Rho activity. Therefore the mechanisms of Rho regulation by FN domains, and the migration-related signals by the IIICS domain will be studied. A better understanding of the mechanisms by which FN supports cell migration is intended to facilitate the development of new therapeutic interventions to help control wound healing and other pathological conditions such as tumor metastasis.