Syndecan-4 signaling in cell-matrix interactions

描述(申请人提供)：细胞从细胞外环境接收到的信号影响它们的附着、扩散、迁移、增殖、存活和形态。这些细胞外信号既可以是自然界中不能溶解的，如来自细胞外基质(ECM)的信号，也可以是可溶的，如生长因子和细胞因子。Syndecan-4是一种跨膜的硫酸乙酰肝素蛋白多糖(HSPG)，在细胞-基质相互作用中作为整合素的共同受体。Syndecan-4还在生长因子信号转导过程中与生长因子受体共同发挥作用。Syndecan-4与细胞外基质分子如纤维连接蛋白和生长因子的相互作用是通过Syndecan-4的硫酸乙酰肝素侧链介导的，并导致Syndecan-4的聚集。我们的总体假设是，这种聚集，反过来，允许特定的细胞质蛋白招募到细胞膜。胞质蛋白Syndesmos与Syndecan-4的胞质结构域发生特异性的相互作用。Syndesmos还结合了Paxlin，这是焦点黏附复合体的一个主要接头蛋白。因此，Syndecan-4-Syndesmos-paxlin的三元复合体在细胞外和细胞内环境之间提供了联系。我们建议通过破坏这些单独的分子相互作用来研究每个二元相互作用(Syndecan-4-Syndesmos和Syndesmos-paxlin)对细胞黏附、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函数。我们还将研究Syndecan-4在细胞间相互作用以及与肌动蛋白细胞骨架相互作用中的作用。 由于细胞与细胞外基质和生长因子的相互作用调节细胞的增殖、迁移、存活和分化，当适当调控时，这些相互作用对于正常发育和伤口愈合是必不可少的。如果不受控制，这些事件可能会导致不受控制的生长和迁移，就像癌症一样。因此，从拟议的研究中获得的信息直接适用于理解癌症中的不受控制的生长和伤口愈合中的受控生长。

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.