Receptor protein tyrosine phosphatases are novel components of a polycystin complex
Receptor protein tyrosine phosphatases are novel components of a polycystin complex
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DOI：
10.1016/j.bbadis.2010.11.006
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发表时间：
2011-10-01
影响因子：
6.2
通讯作者：
Sandford, Richard N.
中科院分区：
文献类型：
--
作者：
Boucher, Catherine A.;Ward, Heather H.;Sandford, Richard N.
常染色体显性多囊肾病（ADPKD）是由编码多囊蛋白-1和多囊蛋白-2的PKD 1和PKD 2突变引起的。多囊蛋白-1是酪氨酸磷酸化的，并调节多种信号通路，包括AP-1，和磷酸酶的身份调节多囊蛋白-1是以前的特点。在这里，我们确定LAR蛋白酪氨酸磷酸酶（RPTP）超家族的成员作为多囊蛋白-1复合体的成员，通过细胞外和细胞内的相互作用介导。多囊蛋白-1的第一胞外PKD 1结构域与RFTP σ的第一IG结构域相互作用，而多囊蛋白-1的多囊蛋白-1 C-末端与RFTP γ的调节性D2磷酸酶结构域相互作用。RPTP之间额外的同型和异型相互作用募集RPTP δ。发现多聚体多囊蛋白复合物定位于纤毛中。RPTP σ和RPTP δ也是多囊蛋白-1/E-钙粘蛋白复合物的一部分，已知其对粘附连接稳定的早期事件很重要。多囊蛋白-1和RPTP γ之间的相互作用在ADPKD细胞中被破坏，而RPTP σ和RFTP δ仍然与E-钙粘蛋白密切相关，主要在细胞内位置。多囊蛋白-1 C-末端是RPTP-γ的体外底物，其使c-Src磷酸化的Y 4237残基去磷酸化并激活AP 1介导的转录。这些数据确定RFTP作为纤毛和粘附复合物中多囊蛋白的新型相互作用伴侣，并证明RFTP γ磷酸酶活性是多囊蛋白依赖性信号传导的分子机制的核心。多囊肾的病因是什么？多囊肾的病因是什么？(C)2010 Elsevier B. V.保留所有权利。
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutation of PKD1 and PKD2 that encode polycystin-1 and polycystin-2. Polycystin-1 is tyrosine phosphorylated and modulates multiple signaling pathways including AP-1, and the identity of the phosphatases regulating polycystin-1 are previously uncharacterized. Here we identify members of the LAR protein tyrosine phosphatase (RPTP) superfamily as members of the polycystin-1complex mediated through extra- and intracellular interactions. The first extracellular PKD1 domain of polycystin-1 interacts with the first Ig domain of RFTP sigma, while the polycystin-1 C-terminus of polycystin-1 interacts with the regulatory D2 phosphatase domain of RFTP gamma. Additional homo- and heterotypic interactions between RPTPs recruit RPTP delta. The multimeric polycystin protein complex is found localised in cilia. RPTP sigma and RPTP delta are also part of a polycystin-1/E-cadherin complex known to be important for early events in adherens junction stabilisation. The interaction between polycystin-1 and RPTP gamma is disrupted in ADPKD cells, while RPTP sigma and RFTP delta remain closely associated with E-cadherin, largely in an intracellular location. The polycystin-1 C-terminus is an in vitro substrate of RPTP-gamma, which dephosphorylates the c-Src phosphorylated Y4237 residue and activates AP1-mediated transcription. The data identify RFTPs as novel interacting partners of the polycystins both in cilia and at adhesion complexes and demonstrate RFTP gamma phosphatase activity is central to the molecular mechanisms governing polycystin-dependent signaling. This article is part of a Special Issue entitled: Polycystic Kidney Disease. (C) 2010 Elsevier B.V. All rights reserved.