Anselmo Anthony N, Earnest Svetlana, Chen Wei, Juang Yu-Chi, Kim Sung Chan, Zhao Yingming, Cobb Melanie H
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10883-8. doi: 10.1073/pnas.0604607103. Epub 2006 Jul 10.
Oxidative stress-responsive kinase (OSR) 1 and sterile20-related, proline-, alanine-rich kinase (SPAK) are Ste20p-related protein kinases that bind to the sodium, potassium, two chloride cotransporter, NKCC. Here we present evidence that the protein kinase with no lysine [K] (WNK) 1 regulates OSR1, SPAK, and NKCC activities. OSR1 exists in a complex with WNK1 in cells, is activated by recombinant WNK1 in vitro, and is phosphorylated in a WNK1-dependent manner in cells. Depletion of WNK1 from HeLa cells by using small interfering RNA reduces OSR1 kinase activity. In addition, depletion of either WNK1 or OSR1 reduces NKCC activity, indicating that WNK1 and OSR1 are both required for NKCC function. OSR1 and SPAK are likely links between WNK1 and NKCC in a pathway that contributes to volume regulation and blood pressure homeostasis in mammals.
氧化应激反应激酶（OSR）1和无菌20相关的富含脯氨酸和丙氨酸的激酶（SPAK）是与Ste20p相关的蛋白激酶，它们与钠钾氯共转运体NKCC结合。在此我们提供证据表明无赖氨酸[K]蛋白激酶（WNK）1调节OSR1、SPAK和NKCC的活性。在细胞中，OSR1与WNK1存在于一个复合物中，在体外被重组WNK1激活，并在细胞中以WNK1依赖的方式被磷酸化。利用小干扰RNA从HeLa细胞中耗尽WNK1会降低OSR1激酶活性。此外，耗尽WNK1或OSR1都会降低NKCC活性，这表明WNK1和OSR1都是NKCC功能所必需的。在有助于哺乳动物体积调节和血压稳态的途径中，OSR1和SPAK可能是WNK1与NKCC之间的联系环节。
