PDZ-mediated signaling through syndecan-4

PDZ 通过 syndecan-4 介导的信号传导

• 批准号: 6545320
• 负责人: Arie Horowitz
• 金额: $ 26.58万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6545320
• 关键词: binding proteins; biological signal transduction; fibroblast growth factor; gene targeting; genetically modified animals; heparan sulfate; laboratory mouse; myocardial infarction; phosphatidylinositols; protein binding; protein protein interaction; syndecan; transcription factor; vascular endothelium; yeast two hybrid system

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.

跨膜受体的羧基末端与接头蛋白的保守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。 跨膜蛋白多糖的多配体家族属于这一大类PDZ结合细胞表面受体。 直到最近，蛋白多糖功能的普遍概念仍集中在其硫酸乙酰肝素链上，作为参与生长因子和细胞外基质蛋白结合的活性成分。然而，由于新发现的结果，这种观点正在被修正，这些新发现表明跨膜蛋白聚糖的多配体家族高度保守的细胞质尾部也参与了由外向内信号的转导。 虽然所有多配体都具有 PDZ 结合羧基末端，但广泛表达的多配体-4 在其胞质尾部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 的激活。 我们实验室的最新研究结果表明，syndecan-4 的细胞质尾部和含有 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至关重要，这一点通过迁移、增殖和细胞迁移受损来证明。当这种相互作用被破坏时，内皮细胞形成血管网络。 该提案的目的是利用最近鉴定的 syndecan-4 PDZ 伙伴 Synectin 作为原型，阐明通过 PDZ-syndecan-4 相互作用的信号传导机制的性质。 这种相互作用是新型 FGF 信号通路的一部分，并形成信号转导调节的新范例。 我们将重点关注 (1) 表征 syndecan-4 和 synectin 之间的结合机制，(2) 识别 syndecan-4 以外的其他 synectin 结合伴侣，以确定 syndecan-4 介导的信号通路的进一步下游成员，以及(3) 通过 Synectin 基因敲除小鼠模型，表征 Synectin 的一般功能，特别是内皮细胞特异性功能。