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首页> 外文期刊>Journal of Cellular Physiology >Down-regulation of MEK/ERK signaling by E-cadherin-dependent PI3K/Akt pathway in differentiating intestinal epithelial cells.
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Down-regulation of MEK/ERK signaling by E-cadherin-dependent PI3K/Akt pathway in differentiating intestinal epithelial cells.

机译：下调MEK / ERK信号E-cadherin-dependent PI3K / Akt通路区分肠道上皮细胞。

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摘要

In vitro experiments have shown that the establishment of cell-cell contacts in intestinal epithelial cell cultures is a critical step in initiating ERK inhibition, cell cycle arrest, and induction of the differentiation process. Herein, we determined the mechanisms through which E-cadherin-mediated cell-cell contacts modulate the ERK pathway in intestinal epithelial cells. We report that: (1) removal of calcium from the culture medium of newly confluent Caco-2/15 cells (30 min, 4 mM EGTA) results in the disruption of both adherens and tight junctions and clearly decreases Akt phosphorylation while increasing MEK and ERK activities. Akt, MEK, and ERK activation levels return to control levels 60 min after calcium restoration; (2) the use of E-cadherin blocking antibodies efficiently prevents Akt phosphorylation and MEK-ERK inhibition after 70 min of calcium restoration; (3) using the PI3K inhibitor LY294002 (15 microM) in calcium switch experiments, we demonstrate that the assembly of adherens junctions activates Akt activity and triggers the inhibition of ERK1/2 activities in a PI3K-dependent manner; (4) adenoviral infection of confluent Caco-2/15 cells with a constitutively active mutant of Akt1 strongly represses ERK1/2 activities; (5) inhibition of PI3K abolishes Akt activity but leads to a rapid and sustained activation of the MEK-ERK1/2 in confluent differentiating Caco-2/15 cells, but not in undifferentiated growing Caco-2/15 cells. Our data suggest that E-cadherin engagement leads to MEK/ERK inhibition in a PI3K/Akt-dependent pathway. This mechanism may account for the role of E-cadherin in proliferation/differentiation transition along the crypt-villus axis of the human intestinal epithelium.
机译：体外实验表明,建立信息联系人在肠道上皮细胞培养是关键一步启动ERK抑制、细胞周期阻滞和诱导分化的过程。我们决定的机制E-cadherin-mediated信息联系人调节肠上皮细胞ERK通路。我们报告:(1)删除的钙培养基的支流Caco-2/15细胞(30分钟,4毫米EGTA)导致的破坏adherens和紧密连接和清楚减少一种蛋白激酶磷酸化而增加MEK和ERK活动。激活水平回归控制水平60分钟钙后恢复;钙粘蛋白抗体阻断有效防止一种蛋白激酶磷酸化和mek erk抑制钙70分钟后恢复;(3)使用PI3K抑制剂LY294002 (15 microM)在钙开关的实验中,我们将演示激活粘合连接处并且组装一种蛋白激酶活动的抑制和触发器ERK1/2活动PI3K-dependent方式;adenoviral Caco-2/15融合细胞的感染持续活跃的Akt1突变强烈压制ERK1/2活动;但抑制PI3K废除Akt活动导致快速和持续的激活在汇合的差异化Caco-2/15 MEK-ERK1/2细胞,但不是在未分化的增长Caco-2/15细胞。接触会导致MEK / ERK的抑制PI3K / Akt-dependent途径。钙粘蛋白的作用增殖和分化过渡人类肠道的crypt-villus轴上皮细胞。

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