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RhoJ integrates attractive and repulsive cues in directional migration of endothelial cells.
The EMBO Journal ( IF 9.4 ) Pub Date : 2020-04-29 , DOI: 10.15252/embj.2019102930
Yoko Fukushima 1, 2 , Koichi Nishiyama 3 , Hiroshi Kataoka 4 , Marcus Fruttiger 5 , Shigetomo Fukuhara 6 , Kohji Nishida 2 , Naoki Mochizuki 7 , Hiroki Kurihara 8 , Shin-Ichi Nishikawa 4 , Akiyoshi Uemura 1, 9
Affiliation  

During angiogenesis, VEGF acts as an attractive cue for endothelial cells (EC s), while Sema3E mediates repulsive cues. Here, we show that the small GTP ase RhoJ integrates these opposing signals in directional EC migration. In the GTP ‐bound state, RhoJ interacts with the cytoplasmic domain of PlexinD1. Upon Sema3E stimulation, RhoJ released from PlexinD1 induces cell contraction. PlexinD1‐bound RhoJ further facilitates Sema3E‐induced PlexinD1‐VEGFR 2 association, VEGFR 2 transphosphorylation at Y1214, and p38 MAPK activation, leading to reverse EC migration. Upon VEGF stimulation, RhoJ is required for the formation of the holoreceptor complex comprising VEGFR 2, PlexinD1, and neuropilin‐1, thereby preventing degradation of internalized VEGFR 2, prolonging downstream signal transductions via PLC γ, Erk, and Akt, and promoting forward EC migration. After conversion to the GDP ‐bound state, RhoJ shifts from PlexinD1 to VEGFR 2, which then terminates the VEGFR 2 signals. RhoJ deficiency in EC s efficiently suppressed aberrant angiogenesis in ischemic retina. These findings suggest that distinct Rho GTP ases may act as context‐dependent integrators of chemotactic cues in directional cell migration and may serve as candidate therapeutic targets to manipulate cell motility in disease or tissue regeneration.

中文翻译:

RhoJ在内皮细胞的定向迁移中整合了吸引和排斥的线索。

在血管生成过程中,VEGF充当内皮细胞(EC s)的诱人信号,而Sema3E介导排斥信号。在这里,我们显示了小的GTP酶RhoJ在定向EC迁移中整合了这些相反的信号。在GTP结合状态下,RhoJ与PlexinD1的胞质域相互作用。在Sema3E刺激后,从PlexinD1释放的RhoJ诱导细胞收缩。结合PlexinD1的RhoJ进一步促进Sema3E诱导的PlexinD1-VEGFR 2缔合,Y1214处的VEGFR 2转磷酸化和p38 MAPK激活,从而导致EC反向迁移。受到VEGF刺激后,RhoJ才能形成包含VEGFR 2,PlexinD1和Neuropilin-1的全息感受器复合物,从而防止内在的VEGFR 2降解,从而延长了通过PLCγ,Erk和Akt的下游信号转导,并促进了正向EC移民。转换为GDP绑定状态后,RhoJ从PlexinD1转换为VEGFR 2,然后终止VEGFR 2信号。EC的RhoJ缺乏症可有效抑制缺血性视网膜的异常血管生成。这些发现表明,不同的Rho GTP驴可能在定向细胞迁移中作为趋化线索的上下文相关整合者,并且可以作为在疾病或组织再生中操纵细胞运动的候选治疗靶点。
更新日期:2020-04-29
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