Targeted deletion of the integrin β4 signaling domain suppresses laminin-5-dependent nuclear entry of mitogen-activated protein kinases and NF-κB, causing defects in epidermal growth and migration
Targeted deletion of the integrin β4 signaling domain suppresses laminin-5-dependent nuclear entry of mitogen-activated protein kinases and NF-κB, causing defects in epidermal growth and migration
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DOI：
10.1128/mcb.25.14.6090-6102.2005
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发表时间：
2005-07-01
影响因子：
5.3
通讯作者：
Giancotti, FG
中科院分区：
文献类型：
--
作者：
Nikolopoulos, SN;Blaikie, P;Giancotti, FG
α 6 β 4整联蛋白-α层粘连蛋白-5受体介导半桥粒的组装以及She和磷酸肌醇3-激酶通过β 4独特的细胞质延伸的募集。携带β 4信号结构域靶向缺失的小鼠发育正常，不会显示皮肤脆弱的迹象。这些小鼠的表皮含有结构良好的半桥粒，并稳定地粘附在基底膜上。然而，由于基底角质形成细胞增殖减少，它发育不良，并且以降低的速率进行伤口修复。来自β 4突变小鼠的角质形成细胞经历广泛的扩散，但不能响应层粘连蛋白-5上的表皮生长因子（EGF）而增殖和迁移。EGF引起细胞外信号调节激酶（ERK）和Jun N-末端蛋白激酶（JNK）的显著磷酸化以及粘附层粘连蛋白-5的β 4突变细胞中I κ B的磷酸化和降解。然而，出乎意料的是，在层粘连蛋白-5上的β 4突变细胞中，ERK、JNK和NF-κ B保留在细胞质中，而在纤连蛋白上的相同细胞中或在两种基质蛋白上的野生型细胞中，它们有效地进入细胞核。抑制剂研究表明，α 6 β 4通过其对NF-κ B和P-JNK的作用促进角质形成细胞增殖和迁移。这些发现提供了证据表明，β 4信号通过以前未认识到的对NF-κ B和促分裂原活化蛋白激酶的核转位的影响促进表皮生长和伤口愈合。
The alpha 6 beta 4 integrin-a laminin-5 receptor-mediates assembly of hemidesmosomes and recruitment of She and phosphoinositide 3-kinase through the unique cytoplasmic extension of beta 4. Mice carrying a targeted deletion of the signaling domain of beta 4 develop normally and do not display signs of skin fragility. The epidermis of these mice contains well-structured hemidesmosomes and adheres stably to the basement membrane. However, it is hypoplastic due to reduced proliferation of basal keratinocytes and undergoes wound repair at a reduced rate. Keratinocytes from beta 4 mutant mice undergo extensive spreading but fail to proliferate and migrate in response to epidermal growth factor (EGF) on laminin-5. EGF causes significant phosphorylation of extracellular signal-regulated kinase (ERK) and Jun N-terminal protein kinase (JNK) and phosphorylation and degradation Of I kappa B in beta 4 mutant cells adhering to laminin-5. Unexpectedly, however, ERK, JNK, and NF-kappa B remain in the cytoplasm in beta 4 mutant cells on laminin-5, whereas they enter effectively into the nucleus in the same cells on fibronectin or in wild-type cells on both matrix proteins. Inhibitor studies indicate that alpha 6 beta 4 promotes keratinocyte proliferation and migration through its effect on NF-kappa B and P-JNK. These findings provide evidence that beta 4 signaling promotes epidermal growth and wound healing through a previously unrecognized effect on nuclear translocation of NF-kappa B and mitogen-activated protein kinases.