The WNK [with no lysine (K)] kinases and their downstream effector kinases, oxidative stress responsive 1 (OSR1) and SPS/STE20-related proline-alanine–rich kinase (SPAK), have well established functions in the maintenance of cell volume and ion homeostasis. Mutations in these kinases have been linked to an inherited form of hypertension, neurologic defects, and other pathologies. A rapidly expanding body of evidence points to the involvement of WNKs in regulating multiple diverse cellular processes as well as the progression of some forms of cancer. How OSR1 and SPAK contribute to these processes is well understood in some cases but completely unknown in others. OSR1 and SPAK are targeted to both WNKs and substrates via their conserved C-terminal (CCT) protein interaction domains. Considerable effort has been put forth to understand the structure, function, and interaction specificity of the CCT domains in relation to WNK signaling, and multiple inhibitors of WNK signaling target these domains. The domains bind RFxV and RxFxV protein sequence motifs with the consensus sequence R-F-x-V/I or R-x-F-x-V/I, but residues outside the core motif also contribute to specificity. CCT interactions are required for OSR1 and SPAK activation and deactivation as well as cation-chloride cotransporter substrate phosphorylation. All four WNKs also contain CCT-like domains that have similar structures and conserved binding residues when compared with CCT domains, but their functions and interaction specificities are mostly unknown. A better understanding of the varied actions of these domains and their interactions will better define the known signaling mechanisms of the WNK pathway as well as uncover new ones.

中文翻译：

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WNK 信号中的 CCT 和 CCT 样模块化蛋白质相互作用域

WNK [不含赖氨酸 (K)] 激酶及其下游效应激酶、氧化应激反应 1 (OSR1) 和 SPS/STE20 相关的富含脯氨酸丙氨酸激酶 (SPAK) 在维持细胞体积方面具有完善的功能和离子稳态。这些激酶的突变与遗传性高血压、神经缺陷和其他病症有关。迅速扩大的证据表明 WNK 参与调节多种不同的细胞过程以及某些形式的癌症的进展。OSR1 和 SPAK 如何促进这些过程在某些情况下已为人们所熟知，但在其他情况下则完全未知。OSR1 和 SPAK 通过其保守的 C 末端 (CCT) 蛋白质相互作用域靶向 WNK 和底物。已经付出了相当大的努力来理解结构，CCT 结构域与 WNK 信号传导相关的功能和相互作用特异性，WNK 信号传导的多种抑制剂靶向这些结构域。这些域将 RFxV 和 RxFxV 蛋白质序列基序与共有序列 RFxV/I 或 RxFxV/I 结合，但核心基序外的残基也有助于特异性。OSR1 和 SPAK 激活和失活以及阳离子-氯化物协同转运蛋白底物磷酸化需要 CCT 相互作用。与 CCT 结构域相比，所有四种 WNK 还包含具有相似结构和保守结合残基的 CCT 样结构域，但它们的功能和相互作用特异性大多未知。