Formation of E-cadherin/β-catenin-based adherens junctions in hepatocytes requires serine-10 in p27(Kip1)
Formation of E-cadherin/β-catenin-based adherens junctions in hepatocytes requires serine-10 in p27(Kip1)
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DOI：
10.1091/mbc.e07-07-0661
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发表时间：
2008-04-01
影响因子：
3.3
通讯作者：
van IJzendoorn, Sven C. D.
中科院分区：
文献类型：
--
作者：
Theard, Delphine;Raspe, Marcel A.;van IJzendoorn, Sven C. D.
粘附连接处上皮细胞之间的粘附受到介导其核心成分的细胞内运输和组装的信号通路的调节。深入了解其分子机制对于了解粘附连接如何促进上皮组织的功能组织是必要的。在此，我们证明在人肝 HepG2 细胞中，制瘤素 M-p42/44 丝裂原激活蛋白激酶信号传导刺激 Ser-10 上的 p27(Kip1) 磷酸化并促进细胞间粘附。 HepG2 细胞中野生型 p27 或磷酸化模拟 p27S10D 突变体的过度表达会诱导超粘附表型。相反，不可磷酸化的p27S10A突变体的过度表达阻止E-钙粘蛋白和β-连环蛋白在细胞表面的动员，降低基底细胞-细胞粘附强度，并阻止制瘤素M对细胞-细胞粘附的刺激作用。作为潜在分子机制的一部分，研究表明，在表达 p27S10A 的细胞中，β-连环蛋白与 p27 相互作用，并被阻止与 E-钙粘蛋白相互作用。在表达 p27S10A 突变体而不是野生型 p27 的 p27S10A 敲入小鼠的肝细胞中也观察到 E-钙粘蛋白和 β-连环蛋白的细胞内保留。总之，这些数据表明肝细胞中粘附连接的形成需要 p27 中的 Ser-10。
The adhesion between epithelial cells at adherens junctions is regulated by signaling pathways that mediate the intracellular trafficking and assembly of its core components. Insight into the molecular mechanisms of this is necessary to understand how adherens junctions contribute to the functional organization of epithelial tissues. Here, we demonstrate that in human hepatic HepG2 cells, oncostatin M-p42/44 mitogen-activated protein kinase signaling stimulates the phosphorylation of p27(Kip1) on Ser-10 and promotes cell -cell adhesion. The overexpression of wild-type p27 or a phospho-mimetic p27S10D mutant in HepG2 cells induces a hyper-adhesive phenotype. In contrast, the overexpression of a nonphosphorylatable p27S10A mutant prevents the mobilization of E-cadherin and beta-catenin at the cell surface, reduces basal cell -cell adhesion strength, and prevents the stimulatory effect of oncostatin M on cell -cell adhesion. As part of the underlying molecular mechanism, it is shown that in p27S10A-expressing cells beta-catenin interacts with p27 and is prevented from interacting with E-cadherin. The intracellular retention of E-cadherin and beta-catenin is also observed in hepatocytes from p27S10A knockin mice that express the p27S10A mutant instead of wild-type p27. Together, these data suggest that the formation of adherens junctions in hepatocytes requires Ser-10 in p27.