金属离子转运蛋白ZIP8，能将胞外和细胞器内的锌离子转运进入细胞浆，在维持锌离子动态平衡方面发挥重要作用，对细胞正常功能的行使至关重要。ZIP8还具有转运镉离子的能力，而镉是一种剧毒且易于积聚不易排泄的重金属致癌物。前期研究中，我们发现在正常培养细胞中，ZIP8蛋白就有一部分会降解，这一降解过程可以被NH4Cl和MG132抑制。另外，还发现ZIP8蛋白水平在镉处理细胞中与p38 MAPK、JNK的磷酸化水平呈潜在的正相关。通过生物信息学分析和pull-down加磷酸蛋白质谱分析，结果显示ZIP8中有4个位点在镉刺激时发生了磷酸化，本项目拟在此基础上，进一步研究阐明每一个磷酸化位点与蛋白激酶p38 MAPK和JNK活性，以及与ZIP8降解的调控关系，在揭示ZIP8调控网络的同时，探讨这一调控机制对镉急性毒性反应、镉诱导细胞转化以及镉诱发肿瘤的药物敏感性等方面的的生物学意义。

The metal ion transporter ZIP8, which is able to transport zinc ion from the extracellular and intracellular organelles into the cytoplasm, plays an important role in maintaining the dynamic balance of zinc homeostasis. ZIP8 also has the ability to import cadmium ion, which is a pervasive and highly toxic heavy metal carcinogen. In our previous studies, we found that cellular, ZIP8 protein stability can be sustained by lysosomal inhibitor (NH4Cl) and/or proteasomal inhibitor (MG132) treatment. In addition, we found that the level of ZIP8 protein was positively correlated with the phosphorylation of p38 MAPK and JNK in cells treated with cadmium. Through bioinformatic and tandem mass spectrometry analyses, four novel phosphorylation sites were identified in ZIP8 upon cadmium treatment. Based on the above, the aim of this project will further focus on delineating the critical phosphorylation site(s) of ZIP8 which correlated with p38 MAPK and JNK activity, and the relationship to the regulation of ZIP8 protein stability and turnover. The results from this study will certainly reveal novel biological insights on the ZIP8 regulatory network and at the same time providing potential measures to antagonize the toxic and carcinogenic effects of cadmium.