Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity.
Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity.
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DOI：
10.1038/ncb1976
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发表时间：
2009-11
影响因子：
21.3
通讯作者：
Li DY
中科院分区：
文献类型：
--
作者：
Jones CA;Nishiya N;London NR;Zhu W;Sorensen LK;Chan AC;Lim CJ;Chen H;Zhang Q;Schultz PG;Hayallah AM;Thomas KR;Famulok M;Zhang K;Ginsberg MH;Li DY
Slit-Roundabout（Robo）信号在轴突引导中具有众所周知的作用。然而，与神经系统不同的是，内皮特异性Robo Robo 4的Slit依赖性激活不会启动引导程序。相反，Robo 4通过抑制促血管生成因子诱导的新生血管簇形成和内皮通透性过高来维持成熟血管网络的屏障功能。在这项研究中，我们使用细胞生物学和生物化学技术来阐明Robo 4维持血管稳定性的分子机制。在这里，我们证明，Robo 4介导的Slit 2依赖性抑制细胞的增殖活性，通过直接与细胞内的衔接蛋白桩蛋白和它的paradenosine，Hic-5的相互作用。Robo 4-桩蛋白复合物在细胞表面的形成阻断了小GTP酶Arf 6的活化，并因此通过募集Arf-GAP（ADP-核糖基化因子-指导的GTP酶-活化蛋白）如GIT 1阻断了Rac的活化。与这些体外研究一致，抑制体内Arf 6活性通过减少脉络膜和视网膜血管疾病中的病理性血管生成和VEGF-165（血管内皮生长因子-165）诱导的视网膜通透性过高来模拟Robo 4活化。这些数据表明，Slit 2-Robo 4-paxillin-GIT 1网络抑制了新血管形成和血管渗漏背后的细胞突起活动，并确定了改善血管系统疾病的新治疗靶点。
Slit–Roundabout (Robo) signalling has a well-understood role in axon guidance. Unlike in the nervous system, however, Slitdependent activation of an endothelial-specific Robo, Robo4, does not initiate a guidance program. Instead, Robo4 maintains the barrier function of the mature vascular network by inhibiting neovascular tuft formation and endothelial hyperpermeability induced by pro-angiogenic factors. In this study, we used cell biological and biochemical techniques to elucidate the molecular mechanism underlying the maintenance of vascular stability by Robo4. Here, we demonstrate that Robo4 mediates Slit2-dependent suppression of cellular protrusive activity through direct interaction with the intracellular adaptor protein paxillin and its paralogue, Hic-5. Formation of a Robo4–paxillin complex at the cell surface blocks activation of the small GTPase Arf6 and, consequently, Rac by recruitment of Arf-GAPs (ADP-ribosylation factor- directed GTPase-activating proteins) such as GIT1. Consistent with these in vitro studies, inhibition of Arf6 activity in vivo phenocopies Robo4 activation by reducing pathologic angiogenesis in choroidal and retinal vascular disease and VEGF-165 (vascular endothelial growth factor-165)-induced retinal hyperpermeability. These data reveal that a Slit2–Robo4–paxillin–GIT1 network inhibits the cellular protrusive activity underlying neovascularization and vascular leak, and identify a new therapeutic target for ameliorating diseases involving the vascular system.
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影响因子：
64.5
作者：
Brose, K;Bland, KS;Kidd, T
通讯作者：
Kidd, T
Rho GTPases控制细胞运动过程中的极性，突出和粘附。
影响因子：
7.8
作者：
Nobes, C D;Hall, A
通讯作者：
Hall, A
影响因子：
2.7
作者：
Park, KW;Morrison, CM;Li, DY
通讯作者：
Li, DY
DOI：
10.1016/j.bbrc.2005.03.250
发表时间：
2005-07-01
影响因子：
3.1
作者：
Seth, P;Lin, YF;Sukhatme, VP
通讯作者：
Sukhatme, VP
DOI：
10.1073/pnas.0702136104
发表时间：
2007-05-01
影响因子：
11.1
作者：
Zhang, Qisheng;Major, Michael B.;Ding, Sheng
通讯作者：
Ding, Sheng