Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45229.
Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):10918-10923. doi: 10.1073/pnas.1704030114. Epub 2017 Sep 25.
Angiogenesis and vascular remodeling are essential for the establishment of vascular networks during organogenesis. Here we show that the Hippo signaling pathway effectors YAP and TAZ are required, in a gene dosage-dependent manner, for the proliferation and migration of vascular endothelial cells (ECs) during retinal angiogenesis. Intriguingly, nuclear translocation of YAP and TAZ induced by /-deletion blocked endothelial migration and phenocopied -deficient mutants. Furthermore, overexpression of a cytoplasmic form of YAP (YAPS127D) partially rescued the migration defects caused by loss of YAP and TAZ function. Finally, we found that cytoplasmic YAP positively regulated the activity of the small GTPase CDC42, deletion of which caused severe defects in endothelial migration. These findings uncover a previously unrecognized role of cytoplasmic YAP/TAZ in promoting cell migration by activating CDC42 and provide insight into how Hippo signaling in ECs regulates angiogenesis.
血管生成和血管重塑对于器官发生过程中血管网络的建立至关重要。在这里，我们表明 Hippo 信号通路效应物 YAP 和 TAZ 在视网膜血管生成过程中，以基因剂量依赖的方式，对血管内皮细胞（EC）的增殖和迁移是必需的。有趣的是，由/-缺失诱导的 YAP 和 TAZ 的核易位阻断了内皮细胞的迁移，并表现出 -缺陷突变体的表型。此外，过表达 YAP 的细胞质形式（YAPS127D）部分挽救了 YAP 和 TAZ 功能缺失引起的迁移缺陷。最后，我们发现细胞质 YAP 正向调节小 GTPase CDC42 的活性，CDC42 的缺失导致内皮细胞迁移严重缺陷。这些发现揭示了细胞质 YAP/TAZ 通过激活 CDC42 促进细胞迁移的先前未被认识的作用，并深入了解 Hippo 信号在 EC 中如何调节血管生成。
