Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization
Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization
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DOI：
10.1172/jci27414
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发表时间：
2006-05-01
影响因子：
15.9
通讯作者：
Holzman, LB
中科院分区：
文献类型：
--
作者：
Verma, R;Kovari, I;Holzman, LB
一个适当建立和维持的足细胞间连接，或狭缝隔膜，是肾小球选择性渗透屏障的必要组成部分。观察到裂膜跨膜蛋白nephrin的突变或缺失导致足细胞足突形态发生的失败和伴随的蛋白尿，首先提出了nephrin作为信号复合物的组分直接整合足细胞连接完整性与细胞骨架动力学的假设。本文所作的观察提供了第一个直接证据，我们的知识磷酸化介导的信号传导机制，这种整合功能的衍生。我们的数据支持的模型，在足细胞间连接的形成，参与nephrin胞外域诱导瞬时Fyn催化活性，导致在nephrin磷酸化的特定nephrin胞质结构域酪氨酸残基。我们发现，这nephrin磷酸化事件导致招聘的SH 2-SH 3结构域的衔接蛋白NCK和组装的肌动蛋白丝在NCK依赖的方式。考虑到nephrin家族蛋白在其他生物体中的作用以及肌动蛋白动力学和连接形成的整体关系，这些观察结果建立了nephrin在调节肌动蛋白细胞骨架动力学中的功能。
A properly established and maintained podocyte intercellular junction, or slit diaphragm, is a necessary component of the selective permeability barrier of the kidney glomerulus. The observation that mutation or deletion of the slit diaphragm transmembrane protein nephrin results in failure of podocyte foot process morphogenesis and concomitant proteinuria first suggested the hypothesis that nephrin serves as a component of a signaling complex that directly integrates podocyte junctional integrity with cytoskeletal dynamics. The observations made herein provide the first direct evidence to our knowledge for a phosphorylation-mediated signaling mechanism by which this integrative function is derived. Our data support the model that during podocyte intercellular junction formation, engagement of the nephrin ectodomain induces transient Fyn catalytic activity that results in nephrin phosphorylation on specific nephrin cytoplasmic domain tyrosine residues. We found that this nephrin phosphorylation event resulted in recruitment of the SH2-SH3 domain-containing adapter protein Nck and assembly of actin filaments in an Nck-dependent fashion. Considered in the context of the role of nephrin family proteins in other organisms and the integral relationship of actin dynamics and junction formation, these observations establish a function for nephrin in regulating actin cytoskeletal dynamics.