Syndecan-4 signaling in cell-matrix interactions

描述（由申请人提供）：细胞从细胞外环境接收的信号影响它们的附着、扩散、迁移、增殖、存活和形态。这些细胞外信号可以是不可溶的，如那些来自细胞外基质（ECM）或可溶的，如生长因子和细胞因子。Syndecan-4是一种跨膜硫酸肝素蛋白聚糖（HSPG），在细胞-基质相互作用中作为整合素的共受体。Syndecan-4在生长因子信号传导过程中也作为生长因子受体的共受体。syndecan-4与纤维连接蛋白等ECM分子以及与生长因子的相互作用是通过syndecan-4的硫酸肝素侧链介导的，并导致syndecan-4聚集。我们的总体假设是，这种聚类反过来又允许特定的细胞质蛋白向细胞膜募集。胞质蛋白syndesmos特异性地与syndecan-4的胞质结构域相互作用。联desmos也结合paxillin，这是一种主要的黏附复合物的衔接蛋白。因此，syndecan-4-syndesmos-paxillin三元配合物提供了细胞外和细胞内环境之间的联系。我们建议通过破坏这些单独的分子相互作用来研究每一个二元相互作用（syndecan-4-syndesmos和syndesmos-paxillin）对细胞粘附、迁移、形态和下游信号事件的贡献，作为细胞外基质和生长因子的功能。我们还将研究syndecan-4在细胞-细胞相互作用以及与肌动蛋白细胞骨架相互作用中的作用。

DESCRIPTION (provided by applicant): 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.