Cell confluence regulates hepatocyte growth factor-stimulated cell morphogenesis in a β-catenin-dependent manner
Cell confluence regulates hepatocyte growth factor-stimulated cell morphogenesis in a β-catenin-dependent manner
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DOI：
10.1128/mcb.01312-06
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发表时间：
2006-12-01
影响因子：
5.3
通讯作者：
Cantley, Lloyd G.
中科院分区：
文献类型：
--
作者：
Ishibe, Shuta;Haydu, J. Erika;Cantley, Lloyd G.
器官损伤后，形态发生上皮反应可能会根据局部细胞密度而变化。在本研究中，检查了细胞汇合在确定肾上皮细胞对肝细胞生长因子（HGF）去分化形态发生信号的反应性中的作用。汇合度的增加导致细胞更倾向于组织成上皮管，并且对 HGF 的迁移反应性显着降低。下游信号传导分析表明，HGF 刺激后，汇合细胞和非汇合细胞中的 HGF 受体 c-Met 均被激活，但汇合细胞中磷酸肌醇 3 激酶依赖性 Akt 和 Rac 的激活选择性减弱。在用 HGF 处理的非汇合细胞中，高水平的 Akt 激活导致糖原合成酶激酶 3 beta (GSK-3 beta) 的抑制性磷酸化，并增加 β-连环蛋白核信号传导。相比之下，汇合细胞中 HGF 刺激的 Akt 激活减弱，GSK-3 β 的抑制性磷酸化和 β-连环蛋白的核信号传导减少。 β-连环蛋白 (SA) 的过度表达（SA）不能被 GSK-3 beta 磷酸化，并且以泛素化为目标，可显着增加完全汇合细胞中的迁移。因此，维持在高汇合状态的细胞选择性下调信号事件，例如 Rac 激活和 β-连环蛋白依赖性转录，否则会促进细胞去分化和迁移。
Following organ injury, morphogenic epithelial responses can vary depending on local cell density. In the present study, the role of cell confluence in determining the responsiveness of renal epithelial cells to the dedifferentiating morphogenic signals of hepatocyte growth factor (HGF) was examined. Increasing confluence resulted in a greater tendency of cells to organize into epithelial tubes and a significant decrease in migratory responsiveness to HGF. Analysis of downstream signaling revealed that the HGF receptor c-Met was equally activated in confluent and nonconfluent cells following HGF stimulation but that phosphoinositide 3-kinase-dependent activation of Akt and Rac were selectively diminished in confluent cells. In nonconfluent cells treated with HGF, the high level of Akt activation resulted in inhibitory phosphorylation of glycogen synthase kinase 3 beta (GSK-3 beta) and increased beta-catenin nuclear signaling. In contrast, confluent cells, in which HGF-stimulated Akt activation was diminished, displayed less inhibitory phosphorylation of GSK-3 beta and less nuclear signaling by beta-catenin. Overexpression of beta-catenin (SA), which cannot be phosphorylated by GSK-3 beta and targeted for ubiquitination, significantly increased migration in fully confluent cells. Thus, cells maintained at high confluence selectively downregulate signaling events such as Rac activation and beta-catenin-dependent transcription that would otherwise promote cell dedifferentiation and migration.