Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
Cancer Res. 2013 Feb 15;73(4):1259-64. doi: 10.1158/0008-5472.CAN-12-4031. Epub 2013 Feb 7.
The pH gradient in normal cells is tightly controlled by the activity of various pH-regulatory membrane proteins including the isoform protein of the Na(+)/H(+) exchanger (NHE1). NHE1 is constitutively active in a neoplastic microenvironment, dysregulating pH homeostasis and altering the survival, differentiation, and proliferation of cancer cells, thereby causing them to become tumorigenic. Cytoplasmic alkalinization in breast cancer cells occurs as a result of increased NHE1 activity and, while much is known about the pathophysiologic role of NHE1 in tumor progression with regard to ion flux, the regulation of its activity on a molecular level is only recently becoming evident. The membrane domain of NHE1 is sufficient for ion exchange. However, its activity is regulated through the phosphorylation of key amino acids in the cytosolic domain as well as by its interaction with other intracellular proteins and lipids. Here, we review the importance of these regulatory sites and what role they may play in the disrupted functionality of NHE1 in breast cancer metastasis.
正常细胞中的 pH 梯度由各种 pH 调节膜蛋白的活性严格控制，包括 Na(+)/H(+)交换体（NHE1）的同工型蛋白。NHE1 在肿瘤微环境中持续活跃，使 pH 动态平衡失调，改变癌细胞的存活、分化和增殖，从而使它们癌变。乳腺癌细胞的细胞质碱化是由于 NHE1 活性增加所致，尽管人们已经了解 NHE1 在肿瘤进展方面对离子通量的病理生理作用，但它在分子水平上的活性调节直到最近才变得明显。NHE1 的膜结构域足以进行离子交换。然而，其活性通过细胞溶质结构域中关键氨基酸的磷酸化以及与其他细胞内蛋白质和脂质的相互作用来调节。在这里，我们回顾了这些调节位点的重要性以及它们在乳腺癌转移中 NHE1 功能障碍中的作用。
