Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility.
Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility.
复制标题
DOI：
10.1038/s41467-018-07172-3
复制
发表时间：
2018-11-16
影响因子：
16.6
通讯作者：
Graupera M
中科院分区：
文献类型：
--
作者：
Angulo-Urarte A;Casado P;Castillo SD;Kobialka P;Kotini MP;Figueiredo AM;Castel P;Rajeeve V;Milà-Guasch M;Millan J;Wiesner C;Serra H;Muixi L;Casanovas O;Viñals F;Affolter M;Gerhardt H;Huveneers S;Belting HG;Cutillas PR;Graupera M
血管生成是一个依赖于血管内皮细胞重排的动态过程，但其潜在机制和功能相关性知之甚少。在这里，我们表明，在血管发育过程中，PI 3 K α调节内皮细胞重排使用PI 3 K α选择性抑制剂和内皮特异性基因缺失的组合，以消除PI 3 K α活性。定量磷酸蛋白质组学以及详细的体内和体外细胞生物学分析表明，PI 3 K信号传导阻止了肌球蛋白磷酸酶靶向-1（MYPT 1）蛋白的NUAK 1依赖性磷酸化，从而允许肌球蛋白轻链磷酸酶（MLCP）活性并最终下调肌动球蛋白收缩性。PI 3 K活性降低增强肌动球蛋白收缩性并损害连接重塑和稳定性。这导致过度拉伸的内皮细胞不能正确地折叠并在脉管系统内形成异常的叠加层。我们的研究结果将PI 3 K/NUAK 1/MYPT 1/MLCP轴定义为调节内皮细胞中肌动球蛋白收缩性的关键途径，通过控制细胞重排支持血管图案化和扩张。血管生成需要动态内皮重排和血管内相对位置的变化。在这里，作者表明PI 3 K/NUAK 1/MYPT 1/MLCP通路调节血管形成过程中内皮细胞中的肌动球蛋白收缩性和细胞重排。
Angiogenesis is a dynamic process relying on endothelial cell rearrangements within vascular tubes, yet the underlying mechanisms and functional relevance are poorly understood. Here we show that PI3Kα regulates endothelial cell rearrangements using a combination of a PI3Kα-selective inhibitor and endothelial-specific genetic deletion to abrogate PI3Kα activity during vessel development. Quantitative phosphoproteomics together with detailed cell biology analyses in vivo and in vitro reveal that PI3K signalling prevents NUAK1-dependent phosphorylation of the myosin phosphatase targeting-1 (MYPT1) protein, thereby allowing myosin light chain phosphatase (MLCP) activity and ultimately downregulating actomyosin contractility. Decreased PI3K activity enhances actomyosin contractility and impairs junctional remodelling and stabilization. This leads to overstretched endothelial cells that fail to anastomose properly and form aberrant superimposed layers within the vasculature. Our findings define the PI3K/NUAK1/MYPT1/MLCP axis as a critical pathway to regulate actomyosin contractility in endothelial cells, supporting vascular patterning and expansion through the control of cell rearrangement. Angiogenesis requires dynamic endothelial rearrangements and relative position changes within the vascular tubes. Here the authors show that a PI3K/NUAK1/MYPT1/MLCP pathway regulates actomyosin contractility in endothelial cells and cellular rearrangement during vascular patterning.
登录
查看更多内容
影响因子：
2.7
作者：
Blum, Yannick;Belting, Heinz-Georg;Affolter, Markus
通讯作者：
Affolter, Markus
LATS1/WARTS磷酸化MyPT1以抵消PLK1并调节哺乳动物有丝分裂进展。
DOI：
10.1083/jcb.201110110
发表时间：
2012-05-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chiyoda T;Sugiyama N;Shimizu T;Naoe H;Kobayashi Y;Ishizawa J;Arima Y;Tsuda H;Ito M;Kaibuchi K;Aoki D;Ishihama Y;Saya H;Kuninaka S
通讯作者：
Kuninaka S
DOI：
10.1042/bj20131152
发表时间：
2014-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Banerjee S;Buhrlage SJ;Huang HT;Deng X;Zhou W;Wang J;Traynor R;Prescott AR;Alessi DR;Gray NS
通讯作者：
Gray NS
影响因子：
9.2
作者：
Abraham, Sabu;Yeo, Margaret;Mavria, Georgia
通讯作者：
Mavria, Georgia
影响因子：
9.2
作者：
Heckel, Emilie;Boselli, Francesco;Vermot, Julien
通讯作者：
Vermot, Julien