Jaykumar Ankita B, Plumber Sakina, Binns Derk, Wichaidit Chonlarat, Luby-Phelps Katherine, Cobb Melanie H
Department of Pharmacology, UT Southwestern Medical Center, Dallas, USA.
Department of Cell Biology, UT Southwestern Medical Center, Dallas, USA.
bioRxiv. 2024 Sep 16:2024.07.31.606092. doi: 10.1101/2024.07.31.606092.
Angiogenesis is essential for remodeling and repairing existing vessels, and this process requires signaling pathways including those controlled by transforming growth factor beta (TGF-β). We have previously reported crosstalk between TGF-β and the protein kinase With No lysine (K) 1 (WNK1). Homozygous disruption of the gene encoding WNK1 results in lethality in mice near embryonic day E12 due to impaired angiogenesis and this defect can be rescued by endothelial-specific expression of an activated form of the WNK1 substrate kinase Oxidative Stress-Responsive 1 (OSR1). However, molecular processes regulated via a collaboration between TGF-β and WNK1/OSR1 are not well understood. Here we show that WNK1 interacts with the E3 ubiquitin ligases SMURF1/2. In addition, we discovered that WNK1 regulates SMURF1/2 protein stability and vice versa. We also demonstrate that WNK1 activity regulates TGF-β receptor levels, in turn, controlling TGF-β signaling.
血管生成对于重塑和修复现有血管至关重要，这一过程需要包括由转化生长因子β（TGF-β）控制的信号通路。我们之前报道过TGF-β与无赖氨酸（K）1蛋白激酶（WNK1）之间的相互作用。编码WNK1的基因纯合缺失会导致小鼠在胚胎期第12天左右因血管生成受损而死亡，这种缺陷可通过内皮特异性表达WNK1底物激酶氧化应激反应1（OSR1）的激活形式来挽救。然而，TGF-β与WNK1/OSR1之间协同调节的分子过程尚不清楚。在这里，我们表明WNK1与E3泛素连接酶SMURF1/2相互作用。此外，我们发现WNK1调节SMURF1/2的蛋白质稳定性，反之亦然。我们还证明WNK1的活性调节TGF-β受体水平，进而控制TGF-β信号传导。
