WNK KINASES IN DEVELOPMENT

 描述(申请人提供)：WNK1/4突变(无赖氨酸[K]酶)可导致常染色体显性遗传性Gordon综合征(又名。假性低醛固酮增多症II)，以高血压、高钾血症为特征，反映了WNK激酶是控制细胞体积和肾脏离子重吸收的Na+/K+/Cl-共转运体(CCCS)的关键调节因子。最近发现，WNK激酶在发育过程中也有重要作用：WNK1缺乏会导致小鼠血管生成缺陷和心房室发育不良，以及神经缺陷会导致人类遗传性感觉和自主神经病II型(HSANII)。至少WNKs的某些功能是保守的，因为最近的证据表明WNKS在小鼠、斑马鱼和果蝇的神经发育中具有功能。我们发现WNKS的单蝇同源基因是典型的Wnt信号的调节因子，这是WNKS的一种意想不到的新功能，似乎在人类细胞中类似。经典的Wnt/β-Catenin信号通路从无脊椎动物到人类都高度保守，在调节包括干细胞在内的不同细胞类型的增殖中具有广泛而重要的作用。有趣的是，Wnt信号的过度激活可以导致 到肺动脉高压。此外，某些具有高β-连环蛋白活性的癌细胞株的增殖依赖于WNK1，这表明WNK1和WNT信号之间存在复杂的联系。WNK激酶在发育过程中的作用以前没有被认识到；因此，WNK在这一背景下如何发挥作用还不清楚。因此，我们将阐明WNK在发育过程中的功能，确定它们在多大程度上受到Wnt信号的调节，并确定这些功能所必需的新的WNK效应因子。我们的研究战略将阐明WNK如何影响器官发生，从而可能对人类心脏病和癌症产生影响。

 DESCRIPTION (provided by applicant): Mutations in WNK1/4 (With No Lysine [K] kinases) cause autosomal dominant Gordon's syndrome (a.k.a. Pseudohypoaldosteronism Type II) characterized by hypertension, hyperkalemia, and reflecting the fact that WNK kinases are critical regulators of Na+/K+/Cl- co-transporters (CCCs) controlling cell volume and ion reabsorption in the kidney. Recently has it become clear that Wnk kinases also have important functions during development: WNK1 deficiency causes angiogenesis defects and hypoplastic atrial and ventricular heart chambers in mice and neural defects causing Hereditary Sensory and Autonomic Neuropathy type II (HSANII) in humans. At least some functions of Wnk kinases are conserved, as recent evidence suggests that Wnks have a function in neural development in mice, zebrafish, and Drosophila. We identified the single fly ortholog of Wnks as a regulator of canonical Wnt signaling, an unexpected and novel function of Wnks that appears to be similar in human cells. The canonical Wnt/β-Catenin signaling pathway is highly conserved from invertebrates to humans and has a broad and essential role in regulating proliferation of different cell types including stem cells. Interestingly, hyperactivation of Wnt signaling can lead to pulmonary arterial hypertension. Furthermore, the proliferation of certain cancer cell lines wit high β-Catenin activity is dependent on WNK1, suggesting an intricate connection between Wnks and Wnt signaling. The role of Wnk kinases during development was previously unrecognized; therefore, how Wnk functions in this context is not understood. We will thus elucidate the functions of Wnk during development, determine the extent to which they are mediated by Wnt signaling, and identify novel Wnk effectors essential for these functions. Our research strategy will shed much needed light on how Wnk affects organogenesis and thus will likely have implications for human heart disease and cancer.