Human homolog of disc-large is required for adherens junction assembly and differentiation of human intestinal epithelial cells
Human homolog of disc-large is required for adherens junction assembly and differentiation of human intestinal epithelial cells
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DOI：
10.1074/jbc.m309843200
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发表时间：
2004-03-12
影响因子：
4.8
通讯作者：
Rivard, N
中科院分区：
文献类型：
--
作者：
Laprise, P;Viel, A;Rivard, N
我们和其他人已经表明，磷脂酰肌醇3-激酶（PI 3 K）被募集到E-钙粘蛋白的参与和激活。这种PI 3 K活化对于粘附连接的完整性和肠上皮细胞分化是必不可少的。在这里，我们提供的证据表明，hDlg，同源的椎间盘大肿瘤抑制因子，是另一个关键的调节粘附连接的完整性和分化的哺乳动物上皮细胞。我们报告如下。1)hDlg与E-钙粘蛋白共定位，但不与ZO-1共定位于肠上皮细胞中细胞-细胞接触的位点。2)肠细胞中RNA（i）降低hDlg表达水平不仅严重改变了粘附连接的完整性，而且还阻止了p85/PI 3 K募集到E-钙粘蛋白介导的细胞-细胞接触中，并抑制蔗糖酶-异麦芽糖酶基因表达。3)PI 3 K和hDlg与E-钙粘蛋白在活的分化肠细胞中的共同大分子复合物中相关。4)这种相互作用需要hDlg与E-钙粘蛋白和与p85/PI 3 K亚基的Src同源结构域2结构域的缔合。5)丝氨酸和苏氨酸残基上的hDlg磷酸化防止其与亚融合细胞中的p85 Src同源结构域2的相互作用，而酪氨酸残基上的hDlg磷酸化是必需的。我们的结论是，hDlg可能是一个决定因素，在E-钙粘蛋白介导的粘附和信号在哺乳动物上皮细胞。
We and others have shown that phosphatidylinositol 3-kinase (PI3K) is recruited to and activated by E-cadherin engagement. This PI3K activation is essential for adherens junction integrity and intestinal epithelial cell differentiation. Here we provide evidence that hDlg, the homolog of disc-large tumor suppressor, is another key regulator of adherens junction integrity and differentiation in mammalian epithelial cells. We report the following. 1) hDlg co-localizes with E-cadherin, but not with ZO-1, at the sites of cell-cell contact in intestinal epithelial cells. 2) Reduction of hDlg expression levels by RNA(i) in intestinal cells not only severely alters adherens junction integrity but also prevents the recruitment of p85/PI3K to E-cadherin-mediated cell-cell contact and inhibits sucrase-isomaltase gene expression. 3) PI3K and hDlg are associated with E-cadherin in a common macromolecular complex in living differentiating intestinal cells. 4) This interaction requires the association of hDlg with E-cadherin and with Src homology domain 2 domains of the p85/PI3K subunit. 5) Phosphorylation of hDlg on serine and threonine residues prevents its interaction with the p85 Src homology domain 2 in subconfluent cells, whereas phosphorylation of hDlg on tyrosine residues is essential. We conclude that hDlg may be a determinant in E-cadherin-mediated adhesion and signaling in mammalian epithelial cells.