Proteolytic cleavage and nuclear translocation of fibrocystin is regulated by intracellular Ca2+ and activation of protein kinase C
Proteolytic cleavage and nuclear translocation of fibrocystin is regulated by intracellular Ca2+ and activation of protein kinase C
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DOI：
10.1074/jbc.m606740200
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发表时间：
2006-11-10
影响因子：
4.8
通讯作者：
Igarashi, Peter
中科院分区：
文献类型：
--
作者：
Hiesberger, Thomas;Gourley, Eric;Igarashi, Peter
纤维囊蛋白是一种功能未知的I型膜蛋白，是常染色体隐性遗传型多囊肾病的致病蛋白。在这里，我们表明，纤维囊蛋白进行调节蛋白水解。几个蛋白水解裂解发生在预测的胞外域，而至少一个裂解发生在细胞质部分。后者产生C-末端胞内片段，其携带核定位信号KRKVSRLAVTGERTATPAPKIPRIT并易位至核。纤维囊蛋白的蛋白水解裂解在极化的内髓集合管细胞（mIMCD-3）的长期培养物中组成性地发生。在这些条件下，蛋白激酶C的活化和细胞内Ca 2+的释放是蛋白水解所必需的。在人胚肾293细胞（HEK-293）的短期培养物中，纤维囊蛋白的蛋白水解切割可通过刺激细胞内Ca 2+释放或蛋白激酶C的活化来引发。这些结果确定了一种新的Ca 2+依赖的途径，信号从位于细胞膜的纤维囊蛋白的细胞核。
Fibrocystin, a type I membrane protein of unknown function, is the protein affected in the autosomal recessive form of polycystic kidney disease. Here we show that fibrocystin undergoes regulated proteolysis. Several proteolytic cleavages occur within the predicted ectodomain, whereas at least one cleavage occurs within the cytoplasmic portion. The latter generates a C-terminal intracellular fragment that harbors the nuclear localization signal KRKVSRLAVTGERTATPAPKIPRIT and translocates to the nucleus. Proteolytic cleavage of fibrocystin occurs constitutively in long term cultures of polarized inner medullary collecting duct cells (mIMCD-3). Activation of protein kinase C and release of intracellular Ca2+ are required for proteolysis under these conditions. In short term cultures of human embryonic kidney 293 cells (HEK-293), proteolytic cleavage of fibrocystin can be elicited by stimulation of intracellular Ca2+ release or activation of protein kinase C. These results identify a novel Ca2+-dependent pathway that signals from fibrocystin located in the cell membrane to the nucleus.