The p38-MAPK/SAPK pathway is required for human keratinocyte migration on dermal collagen
The p38-MAPK/SAPK pathway is required for human keratinocyte migration on dermal collagen
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DOI：
10.1046/j.0022-202x.2001.01608.x
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发表时间：
2001-12-01
影响因子：
6.5
通讯作者：
Woodley, D
中科院分区：
文献类型：
--
作者：
Li, W;Nadelman, C;Woodley, D
人角质细胞的运动在人皮肤创面的再上皮化过程中起着重要作用。人角质形成细胞迁移的伤口床富含细胞外基质，如纤维蛋白、纤维连接蛋白和胶原蛋白，以及血清因子，如血小板来源的生长因子和转化生长因子β 1。细胞外基质和血清因子与细胞表面受体结合，并启动一系列调节细胞迁移的细胞内信号事件。在这项研究中，我们发现了一个介导胶原蛋白驱动的人角质形成细胞运动的细胞内信号通路。药理抑制p38- α和p38- β丝裂原激活的蛋白激酶的激活可以有效地阻断胶原驱动的人角质细胞迁移。用p38- α或p38- β丝裂原活化蛋白激酶激酶阴性突变体转染相同的角质形成细胞，可显著抑制角质形成细胞在胶原上的迁移。角质形成细胞附着于胶原活化p38丝裂原活化蛋白激酶，以及p44/p42 ERKs。有趣的是，通过过表达构成活性的MKK3和MKK6、MKK3b(E)和MKK6b(E)激活p38丝裂原激活的蛋白激酶级联，既不能在缺乏胶原的情况下启动迁移，也不能增强胶原驱动的迁移。本研究提供的证据表明，p38-MAPK/SAPK途径是必要的，但不足以介导人角质细胞在胶原蛋白上的迁移。
Human keratinocyte motility plays an important role in the re-epithelialization of human skin wounds. The wound bed over which human keratinocytes migrate is rich in extracellular matrices, such as fibrin, fibronectin, and collagen, and serum factors, such as platelet-derived growth factor and transforming growth factor beta1. Extracellular matrices and the serum factors bind to cell surface receptors and initiate a cascade of intracellular signaling events that regulate cell migration. In this study, we identified an intracellular signaling pathway that mediates collagen-driven motility of human keratinocytes. Pharmacologic inhibition of the activation of p38-alpha and p38-beta mitogen-activated protein kinase activation potently blocked collagen-driven human keratinocyte migration. Transfection of the same keratinocytes with the kinase-negative mutants of p38-alpha or p38-beta mitogen-activated protein kinase markedly inhibited keratinocyte migration on collagen. Attachment of keratinocytes to collagen activated p38 mitogen-activated protein kinase, as well as p44/p42 ERKs. Interestingly, activation of the p38 mitogen-activated protein kinase cascade by overexpressing the constitutively active MKK3 and MKK6, MKK3b(E) and MKK6b(E), could neither initiate migration in the absence of collagen nor enhance collagen-driven migration. This study provides evidence that the p38-MAPK/SAPK pathway is necessary, but insufficient, for mediating human keratinocyte migration on collagen.