Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, Shandong University, School of Medicine, Jinan, Shandong 250012, China.
Sci Rep. 2013;3:2333. doi: 10.1038/srep02333.
The heavy metal cadmium is a non-degradable pollutant. By screening the effects of a panel of metal ions on the phosphatase activity, we unexpectedly identified cadmium as a potent inhibitor of PPM1A and PPM1G. In contrast, low micromolar concentrations of cadmium did not inhibit PP1 or tyrosine phosphatases. Kinetic studies revealed that cadmium inhibits PPM phosphatases through the M1 metal ion binding site. In particular, the negative charged D441 in PPM1G specific recognized cadmium. Our results suggest that cadmium is likely a potent inhibitor of most PPM family members except for PHLPPs. Furthermore, we demonstrated that cadmium inhibits PPM1A-regulated MAPK signaling and PPM1G-regulated AKT signaling potently in vivo. Cadmium reversed PPM1A-induced cell cycle arrest and cadmium insensitive PPM1A mutant rescued cadmium induced cell death. Taken together, these findings provide a better understanding of the effects of the toxicity of cadmium in the contexts of human physiology and pathology.
重金属镉是一种不可降解的污染物。通过筛选一组金属离子对磷酸酶活性的影响，我们出人意料地发现镉是 PPM1A 和 PPM1G 的有效抑制剂。相比之下，低微摩尔浓度的镉不会抑制 PP1 或酪氨酸磷酸酶。动力学研究表明，镉通过 M1 金属离子结合位点抑制 PPM 磷酸酶。特别是，PPM1G 中的负电荷 D441 特异性识别镉。我们的研究结果表明，镉很可能是大多数 PPM 家族成员（除了 PHLPPs 之外）的有效抑制剂。此外，我们证明镉在体内强烈抑制 PPM1A 调节的 MAPK 信号和 PPM1G 调节的 AKT 信号。镉逆转了 PPM1A 诱导的细胞周期停滞，而对镉不敏感的 PPM1A 突变体挽救了镉诱导的细胞死亡。总之，这些发现为理解镉在人类生理学和病理学背景下的毒性作用提供了更好的认识。
