Signals received by cells from their extracellular environment influence their attachment, spreading, migration, proliferation, survival and morphology. These extracellular signals can either be insoluble in nature such as those derived from the extracellular matrix (ECM) or soluble as with growth factors and cytokines. Syndecan-4 is a transmembrane heparan sulfate proteoglycan (HSPG) that acts as a co-receptor with integrins in cell-matrix interactions. Syndecan-4 also acts as a co-receptor with growth factor receptors during growth factor signaling. The interactions of syndecan-4 with ECM molecules such as fibronectin and with growth factors are mediated through the heparan sulfate side chains of syndecan-4 and result in the clustering of syndecan-4. Our overall hypothesis is that this clustering, in turn, permits the recruitment of specific cytoplasmic proteins to the cell membrane. The cytoplasmic protein syndesmos specifically interacts with the cytoplasmic domain of syndecan-4. Syndesmos also binds paxillin, a major adaptor protein of the focal adhesion complex. Thus, the ternary complex of syndecan-4-syndesmos-paxillin provides a link between the extracellular and the intracellular environments. We propose to investigate the contributions of each binary interaction (syndecan-4-syndesmos and syndesmos-paxillin) on cell adhesion, migration, morphology and downstream signaling events as a function of the extracellular matrix and growth factors by disrupting these individual molecular interactions. We will also investigate the role of syndecan-4 in cell-cell interactions and in interactions with the actin cytoskeleton. Since the interactions of cells with the ECM and growth factors regulate cell proliferation, migration, survival and differentiation, these interactions, when properly regulated, are essential for normal development and wound healing. When unregulated these events can result in uncontrolled growth and migration as in cancer. The information gained from the proposed studies, therefore, is directly applicable to the understanding of uncontrolled growth as in cancer and controlled growth as in wound healing.
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