Zinc is required for the regulation of proliferation, metabolism, and cell signaling. It is an intracellular second messenger, and the cellular level of ionic, mobile zinc is strictly controlled by zinc transporters. In mammals, zinc homeostasis is primarily regulated by ZIP and ZnT zinc transporters. The importance of these transporters is underscored by the list of diseases resulting from changes in transporter expression and activity. However, despite numerous structural studies of the transporters revealing both zinc binding sites and motifs important for transporter function, the exact molecular mechanisms regulating ZIP and ZnT activities are still not clear. For example, protein phosphorylation was found to regulate ZIP7 activity resulting in the release of Zn²⁺ from intracellular stores leading to phosphorylation of tyrosine kinases and activation of signaling pathways. In addition, sequence analyses predict all 24 human zinc transporters to be phosphorylated suggesting that protein phosphorylation is important for regulation of transporter function. This review describes how zinc transporters are implicated in a number of important human diseases. It summarizes the current knowledge regarding ZIP and ZnT transporter structures and points to how protein phosphorylation seems to be important for the regulation of zinc transporter activity. The review addresses the need to investigate the role of protein phosphorylation in zinc transporter function and regulation, and argues for a pressing need to introduce quantitative phosphoproteomics to specifically target zinc transporters and proteins involved in zinc signaling. Finally, different quantitative phosphoproteomic strategies are suggested.

锌是调节增殖、代谢和细胞信号传导所必需的。它是细胞内的第二信使，离子、可移动锌的细胞水平受到锌转运蛋白的严格控制。在哺乳动物中，锌稳态主要由 ZIP 和 ZnT 锌转运蛋白调节。由转运蛋白表达和活性变化引起的疾病清单强调了这些转运蛋白的重要性。然而，尽管对转运蛋白的大量结构研究揭示了锌结合位点和对转运蛋白功能很重要的基序，但调节 ZIP 和 ZnT 活性的确切分子机制仍不清楚。例如，发现蛋白质磷酸化可调节 ZIP7 活性，导致 Zn ²⁺的释放从细胞内储存导致酪氨酸激酶磷酸化和信号通路激活。此外，序列分析预测所有 24 种人类锌转运蛋白都被磷酸化，表明蛋白质磷酸化对于转运蛋白功能的调节很重要。这篇综述描述了锌转运蛋白如何与许多重要的人类疾病有关。它总结了当前关于 ZIP 和 ZnT 转运蛋白结构的知识，并指出蛋白质磷酸化似乎对锌转运蛋白活性的调节很重要。该评论解决了研究蛋白质磷酸化在锌转运蛋白功能和调节中的作用的必要性，并认为迫切需要引入定量磷酸化蛋白质组学来专门针对锌转运蛋白和参与锌信号传导的蛋白质。最后，建议了不同的定量磷酸化蛋白质组学策略。