Activation of the planar cell polarity formin DAAM1 leads to inhibition of endothelial cell proliferation, migration, and angiogenesis
Activation of the planar cell polarity formin DAAM1 leads to inhibition of endothelial cell proliferation, migration, and angiogenesis
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DOI：
10.1073/pnas.1001075107
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发表时间：
2010-04-13
影响因子：
11.1
通讯作者：
Crews, Craig M.
中科院分区：
文献类型：
--
作者：
Ju, Rong;Cirone, Pasquale;Crews, Craig M.
Wnt/平面细胞极性（PCP）途径调节发育期间的定向细胞运动，并且最近发现在内皮细胞增殖和血管生成中起关键作用[Zhang Y，et al.（2006）Chem Biol 13：1001-1009; Masckauchan TN，et al.（2006）Mol Biol Cell 17：5163-5172]。然而，PCP信号成分调节血管生成的机制仍然未知。我们报道了一个组成型活性的形态发生相关激活因子1（DAAM 1）的C末端结构域的表达选择性地抑制内皮细胞增殖。此外，这种激活的结构抑制内皮细胞迁移和在体内和体外形成协调网络的能力。虽然组成型活性DAAM 1（CDAAM 1）诱导肌动蛋白聚合和微管（MT）的稳定，稳定的MT单独足以抑制内皮细胞的生长选择性。单独抑制肌动蛋白聚合的jasplakinastine治疗未能重现CDAAM 1的抑制作用。这些结果表明，DAAM 1调节内皮细胞的生长，通过MT稳定在细胞类型选择性的方式，并表明PCP信号在血管生成中起着关键作用，通过调节MT稳定。
The Wnt/planar cell polarity (PCP) pathway regulates directed cell movement during development and was recently found to play a critical role in endothelial cell proliferation and angiogenesis [Zhang Y, et al. (2006) Chem Biol 13: 1001-1009; Masckauchan TN, et al. (2006) Mol Biol Cell 17: 5163-5172]. However, the mechanisms by which PCP signaling components regulate angiogenesis remain unknown. We report that expression of a constitutively active Cterminal domain of Dishevelled-associated activator of morphogenesis 1 (DAAM1) selectively inhibited endothelial cell proliferation. Moreover, this activated construct suppressed endothelial cell migration and the ability to form coordinated networks in vivo and in vitro. Although constitutively active DAAM1 (CDAAM1) induced both actin polymerization and microtubule (MT) stabilization, the stabilization of MTs alone was sufficient to inhibit endothelial cell growth selectively. Inhibition of actin polymerization alone by jasplakinolide treatment failed to reproduce the inhibitory effects of CDAAM1. These results indicate that DAAM1 regulates endothelial cell growth through MT stabilization in a cell type-selective manner and suggest that PCP signaling plays a pivotal role in angiogenesis by regulating MT stabilization.