PDZ-mediated signaling through syndecan-4

跨膜受体的羧基末端与衔接蛋白的保守PDZ结合模块之间的相互作用已成为组织信号转导蛋白复合物的主要机制。 跨膜蛋白聚糖的多配体蛋白聚糖家族属于这一大组PDZ结合细胞表面受体。 直到最近，蛋白聚糖功能的一般概念集中在它们的硫酸乙酰肝素链上，作为参与生长因子和细胞外基质蛋白结合的活性组分。这种观点正在进行修订，但是，作为一个新出现的结果，这表明，高度保守的跨膜蛋白聚糖家族的胞质尾巴也参与了由外向内的信号转导。 虽然所有的多配体蛋白聚糖都具有PDZ结合羧基末端，但广泛表达的多配体蛋白聚糖-4在其胞质尾区含有独特的磷脂酰肌醇4，5-二磷酸结合结构域，并促进蛋白激酶C α的活化。 我们实验室的最新发现表明，syndecan-4的胞质尾区与含PDZ结构域的蛋白质之间的相互作用对于细胞对碱性成纤维细胞生长因子的反应是必不可少的，如通过在这种相互作用被破坏时内皮细胞的迁移、增殖和血管网络形成的损害所证明的。 本提案的目的是阐明通过PDZ-多配体蛋白聚糖-4相互作用的信号传导机制的性质，采用最近确定的多配体蛋白聚糖-4 PDZ伴侣连接蛋白作为原型。 这种相互作用是一种新的FGF信号通路的一部分，并形成了一个新的模式，调节信号转导。 我们将集中在（1）之间的syndecan-4和synectin的结合机制的特点，（2）确定其他syndecan-4以外的synectin的结合伙伴，以确定syndecan-4介导的信号通路的进一步下游成员，和（3）的synectin的功能一般，特别是内皮细胞特异性的，通过synectin基因敲除小鼠模型。

The interaction between the carboxy terminus of transmembrane receptors with the conserved PDZ binding module of adaptor proteins has emerged as a major mechanism of organizing signal-transduction protein complexes. The syndecan family of transmembrane proteoglycans belongs to this large group of PDZ- binding cell surface receptors. Until recently, the generally held concept of proteoglycan functions was centered on their heparan sulfate chains as the active component involved in binding of growth factors and of extracellular matrix proteins. This view is undergoing a revision, however, as a consequence of newly emerging findings, which suggest that the highly conserved cytoplasmic tails of the syndecan family of transmembrane proteoglycans also participate in the transduction of outside-in signals. While all the syndecans possess a PDZ-binding carboxy- terminus, the widely expressed syndecan-4 contains a unique phosphatidylinositol 4,5-bisphosphate binding domain in its cytoplasmic tail, and facilitates the activation of protein kinase C alpha. Recent findings from our laboratory indicate that the interaction between the cytoplasmic tail of syndecan-4 and PDZ domain-containing protein(s) is essential for the cellular response to basic fibroblast growth factor, as demonstrated by the impairment of migration, of proliferation, and of vascular network formation by endothelial cells upon the disruption of this interaction. The objective of this proposal is to elucidate the nature of the signaling mechanism through the PDZ-syndecan-4 interaction, employing the recently identified syndecan-4 PDZ partner synectin as a prototype. This interaction is part of a novel FGF signaling pathway, and forms a new paradigm for the regulation of signal transduction. We will focus on (1) characterizing the binding mechanism between syndecan-4 and synectin, (2) identifying additional synectin binding partners other than syndecan-4, in order to determine further downstream members of the syndecan-4-mediated signaling pathway, and (3) characterize the functions of synectin in general, and the endothelial cell-specific ones in particular, by a synectin gene knockout mouse model.