Phosphoinositide 3-kinase signaling to Akt promotes keratinocyte differentiation versus death
Phosphoinositide 3-kinase signaling to Akt promotes keratinocyte differentiation versus death
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DOI：
10.1074/jbc.m506119200
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发表时间：
2005-09-23
影响因子：
4.8
通讯作者：
Goetinck, PF
中科院分区：
文献类型：
--
作者：
Calautti, E;Li, J;Goetinck, PF
调节表皮细胞分化程序的信号通路与那些在凋亡过程中被激活的信号通路有广泛的重叠。然而，分化细胞如何保护自己免受过早死亡的影响，仍然没有明确的定义。我们的研究表明，在小鼠角质形成细胞分化的早期阶段，无论是在培养中还是在活体完整的表皮中，磷脂酰肌醇3-激酶(PI3K)/Akt通路都被激活。角质形成细胞中活性Akt的表达促进生长停滞和分化，而药物阻断PI3K则抑制“晚期”分化标志物的表达，并导致原本会分化的细胞死亡。从机制上讲，角质形成细胞分化过程中PI3K/Akt通路的激活依赖于表皮生长因子受体和酪氨酸激酶Src家族的活性以及E-钙粘附素介导的黏附的参与。在这个过程中，PI3K越来越多地与含有酪氨酸磷酸化YXXM基序的钙粘蛋白-连环蛋白复合体结合。因此，PI3K信号通路在酪氨酸激酶和钙粘附素相关连环蛋白之间的串扰中调节表皮细胞分化和死亡之间的选择。
Signaling pathways regulating the differentiation program of epidermal cells overlap widely with those activated during apoptosis. How differentiating cells remain protected from premature death, however, is still poorly defined. We show here that the phosphoinositide 3-kinase ( PI3K)/ Akt pathway is activated at early stages of mouse keratinocyte differentiation both in culture and in the intact epidermis in vivo. Expression of active Akt in keratinocytes promotes growth arrest and differentiation, whereas pharmacological blockade of PI3K inhibits the expression of "late" differentiation markers and leads to death of cells that would otherwise differentiate. Mechanistically, the activation of the PI3K/Akt pathway in keratinocyte differentiation depends on the activity of the epidermal growth factor receptor and Src families of tyrosine kinases and the engagement of E- cadherin- mediated adhesion. During this process, PI3K associates increasingly with cadherin- catenin protein complexes bearing tyrosine phosphorylated YXXM motifs. Thus, the PI3K signaling pathway regulates the choice between epidermal cell differentiation and death at the cross-talk between tyrosine kinases and cadherin- associated catenins.