VCAM-1 inhibits TGFβ stimulated epithelial-mesenchymal transfonnation by modulating Rho activity and stabilizing intercellular adhesion in epicardial mesothelial cells
VCAM-1 inhibits TGFβ stimulated epithelial-mesenchymal transfonnation by modulating Rho activity and stabilizing intercellular adhesion in epicardial mesothelial cells
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DOI：
10.1016/j.ydbio.2006.08.054
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发表时间：
2006-11-15
影响因子：
2.7
通讯作者：
Dettman, Robert W.
中科院分区：
文献类型：
--
作者：
Dokic, Danijela;Dettman, Robert W.
上皮-间充质转化（epithelial-mesenchymal transformation， EMT）的调控在正常发育和疾病中都是至关重要的。在心脏发育过程中，心外膜浅层间皮细胞经历EMT形成冠状血管和心脏成纤维细胞的前体细胞。在这里，我们报道了α (4) β(1)整合素配体VCAM-1抑制TGF β亚型刺激的鸡心外膜间皮细胞的EMT。我们利用培养的鸡胚和大鼠成年心外膜间皮细胞进一步研究了这种抑制作用的分子基础。我们观察到VCAM-1增加了细胞间连接处的皮质肌动蛋白丝，减少了心外膜细胞的应力纤维。VCAM-1抑制TGF β 1、TGF β 2、TGF β 3和溶血磷脂酸对应激纤维的形成，改变TGF β 3刺激的Rho活性。这伴随着p190RhoGAP酪氨酸磷酸化的增加。这三种TGF β亚型均能减弱细胞间粘附，降低β -catenin和E-cadherin的膜定位，刺激鸡心外膜EMT。同时使用vcam - 1治疗，这些影响均受到限制。我们的数据支持了vcam - 1可以在两个关键点上改变心外膜EMT的假设：它限制了rho依赖性事件，如应力纤维的形成，并维持了β -连环蛋白和e -钙粘蛋白与粘附连接的关联。(c) 2006爱思唯尔公司版权所有。
Regulation of epithelial-mesenchymal transformation (EMT) is of central importance both in normal development and in disease. During heart development, cells of the superficial epicardial mesothelium undergo EMT to give rise to precursor cells of the coronary vasculature and cardiac fibroblasts. Here we report that the alpha(4)beta(1) integrin ligand, VCAM-1, inhibits EMT of chick epicardial mesothelial cells stimulated by TGF beta isoforms. We further investigated the molecular basis of this inhibition using cultured chick embryonic and rat adult epicardial mesothelial cells. We observed that VCAM-1 increased cortical actin filaments at intercellular junctions and reduced stress fibers across epicardial cells. VCAM-1 inhibited stress fiber formation by TGF beta 1, TGF beta 2, TGF beta 3 and lysophosphatidic acid and altered Rho activity stimulated by TGF beta 3. This was accompanied by an increase in tyrosine phosphorylation of p190RhoGAP. All three TGF beta isoforms weakened intercellular adhesion, reduced membrane localization of beta-catenin and E-cadherin and stimulated epicardial EMT in chick hearts. Each of these effects was restricted by simultaneous VCAM-I treatment. Our data support the hypothesis that VCAM-I can alter epicardial EMT at two key points: it limits Rho-dependent events such as stress fiber formation and it maintains the association of beta-catenin and E-cadherin with the adherens junction. (c) 2006 Elsevier Inc. All rights reserved.