Department of Biochemistry, University Alberta, Edmonton, AB T6G 2H7, Canada.
Int J Mol Sci. 2019 May 14;20(10):2378. doi: 10.3390/ijms20102378.
The human Na/H exchanger isoform 1 (NHE1) is a plasma membrane transport protein that plays an important role in pH regulation in mammalian cells. Because of the generation of protons by intermediary metabolism as well as the negative membrane potential, protons accumulate within the cytosol. Extracellular signal-regulated kinase (ERK)-mediated regulation of NHE1 is important in several human pathologies including in the myocardium in heart disease, as well as in breast cancer as a trigger for growth and metastasis. NHE1 has a N-terminal, a 500 amino acid membrane domain, and a C-terminal 315 amino acid cytosolic domain. The C-terminal domain regulates the membrane domain and its effects on transport are modified by protein binding and phosphorylation. Here, we discuss the physiological regulation of NHE1 by ERK, with an emphasis on the critical effects on structure and function. ERK binds directly to the cytosolic domain at specific binding domains. ERK also phosphorylates NHE1 directly at multiple sites, which enhance NHE1 activity with subsequent downstream physiological effects. The NHE1 cytosolic regulatory tail possesses both ordered and disordered regions, and the disordered regions are stabilized by ERK-mediated phosphorylation at a phosphorylation motif. Overall, ERK pathway mediated phosphorylation modulates the NHE1 tail, and affects the activity, structure, and function of this membrane protein.
人源 Na+/H+ 交换体亚型 1（NHE1）是一种质膜转运蛋白，在哺乳动物细胞的 pH 调节中发挥着重要作用。由于中间代谢产生质子以及膜电位为负，质子在细胞质中积累。细胞外信号调节激酶（ERK）介导的 NHE1 调节在包括心脏病中心肌在内的几种人类病理学中很重要，以及在乳腺癌中作为生长和转移的触发因素。NHE1 具有 N 端、500 个氨基酸的膜结构域和 315 个氨基酸的 C 端胞质结构域。C 端结构域调节膜结构域，其对转运的影响通过蛋白结合和磷酸化进行修饰。在这里，我们讨论了 ERK 对 NHE1 的生理调节，重点介绍了对结构和功能的关键影响。ERK 在特定结合域直接与胞质结构域结合。ERK 还直接在多个位点磷酸化 NHE1，这增强了 NHE1 的活性，随后产生下游生理效应。NHE1 胞质调节尾具有有序区和无序区，无序区通过 ERK 介导的磷酸化在磷酸化模体处稳定。总体而言，ERK 途径介导的磷酸化调节 NHE1 尾，影响该膜蛋白的活性、结构和功能。
