Hyperphosphorylation of polycystin-2 at a critical residue in disease reveals an essential role for polycystin-1-regulated dephosphorylation.
Hyperphosphorylation of polycystin-2 at a critical residue in disease reveals an essential role for polycystin-1-regulated dephosphorylation.
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DOI：
10.1093/hmg/ddt031
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发表时间：
2013-02
影响因子：
3.5
通讯作者：
A. Streets;O. Wessely;D. Peters;A. Ong
中科院分区：
文献类型：
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作者：
A. Streets;O. Wessely;D. Peters;A. Ong
PKD 1（85%）或PKD 2（15%）突变几乎可以解释所有常染色体显性多囊肾病（ADPKD）病例。ADPKD蛋白，称为多囊蛋白-1（PC 1）和多囊蛋白-2（PC 2），通过其C-末端相互作用形成受体-离子通道复合物，其功能和调节尚未完全了解。在这里，我们报告了PC 2中的第一个磷酸化残基（Ser（829）），其去磷酸化是由PC 1通过蛋白磷酸酶-1 α（PP 1 α）的募集结合介导的。使用一种新的磷酸化特异性抗体（pPC 2），这个网站，我们证明，丝氨酸（829）是磷酸化的蛋白激酶A（PKA），但仍然组成性磷酸化的细胞和组织缺乏PC 1。cAMP以时间依赖性方式增加MDCK细胞中pSer（829）的基底外侧定位，并且对于爪蟾胚胎中原肾的发育是必需的。当组成型表达时，在周期细胞中观察到与增强的ATP依赖性ER Ca（2+）释放和生长抑制丧失相关的复杂表型。这些结果揭示了一个相互的功能联系之间的PC 1和PC 2，这是严重依赖于它们的相互作用。在没有功能性PC 1的情况下，非相对cAMP刺激PC 2的过度磷酸化可能有助于PKD 1患者的囊肿形成，并代表了理解ADPKD发病机制的新分子范式。
Mutations in PKD1 (85%) or PKD2 (15%) account for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). The ADPKD proteins, termed as polycystin-1 (PC1) and polycystin-2 (PC2), interact via their C-termini to form a receptor-ion channel complex whose function and regulation are not fully understood. Here, we report the first phosphorylated residue (Ser(829)) in PC2, whose dephosphorylation is mediated by PC1 binding through the recruitment of protein phosphatase-1 alpha (PP1α). Using a new phosphospecific antibody (pPC2) to this site, we demonstrate that Ser(829) is phosphorylated by Protein kinase A (PKA) but remains constitutively phosphorylated in cells and tissues lacking PC1. cAMP increased pSer(829) basolateral localization in MDCK cells in a time dependent manner and was essential for pronephric development in Xenopus embryos. When constitutively expressed, a complex phenotype associated with enhanced ATP-dependent ER Ca(2+) release and loss of growth suppression was observed in cycling cells. These results reveal a reciprocal functional link between PC1 and PC2 which is critically dependent on their interaction. Unopposed cAMP stimulated hyperphosphorylation of PC2 in the absence of functional PC1 could contribute to cyst initiation in PKD1 patients and represents a new molecular paradigm in understanding ADPKD pathogenesis.