Cell-matrix interactions have been shown to regulate cell morphology, proliferation, migration, survival, differentiation and matrix assembly. One model for studying cell-matrix interactions involves plating cells on defined extracellular components. Thus, when fibroblasts are plated on fibronectin, they adhere, spread, form specialized structures called focal adhesions and they organized their actin cytoskeleton. There are at least two signaling pathways involved in these cellular events. One pathway involves integrins and the small GTP-binding protein rho. Integrin signaling results from interactions of cells with the cell binding domain of fibronectin. A second signaling pathway involves a cell surface heparin sulfate proteoglycan (HSPG) and results from interactions of the cell with the heparin binding domain of fibronectin. Syndecan 4 is the HSPG of focal adhesions. We have identified a novel cytoplasmic, syndesmos, which interacts with the cytoplasmic domain of syndecan-4. Both syndecan-4 and syndesmos interact with PKC-alpha and syndesmos, PKC and paxillin are part of the second signaling pathway that lead to focal adhesions and actin stress fiber formation when cells interact with fibronectin. The proposal is divided in five specific aims designed to test this hypothesis. Specifically it is proposed to analyze the molecular basis for the interactions among four molecules. The structural information gained from these analyses will be used to determine the functional significance of the structural features responsible for the interactions. This will be done in cell culture using chicken embryos fibroblasts and an avian retroviral expression system and also in mice where we propose to disrupt the genes for syndecan 4 and syndesmos by homologous recombination in ES cells. Since cell-matrix interactions regulate cell proliferation, migration, survival and differentiation these biological events are essential for normal development and they also play an important role in wound healing. When unregulated, these events can result in uncontrolled cell growth and migration as in cancer. The assembly of focal adhesions and the formation of actin stress fibers in cultured cells has been viewed as a model system for would contraction. The information obtained from the proposed studies, therefore, may be applicable to the understanding of uncontrolled growth as in cancer or controlled growth as in wound healing.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Pathobiochemistry Study Section (PBC)
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Klein, Steven
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Massachusetts General Hospital
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