A role for MEK kinase 1 in TGF-β/activin-induced epithelium movement and embryonic eyelid closure
A role for MEK kinase 1 in TGF-β/activin-induced epithelium movement and embryonic eyelid closure
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DOI：
10.1093/emboj/cdg440
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发表时间：
2003-09-01
期刊：
影响因子：
11.4
通讯作者：
Xia, Y
中科院分区：
文献类型：
--
作者：
Zhang, L;Wang, W;Xia, Y
mekk1缺陷小鼠在出生时表现出由胚胎眼睑闭合损伤引起的睁眼表型。MEK激酶1 （MEKK1）在生长中的眼睑上皮顶端高度表达，在野生型小鼠中，眼睑上皮表现出松散的细胞间接触和突出的f -肌动蛋白纤维，但在MEKK1缺陷小鼠中，细胞接触紧密，缺乏聚合肌动蛋白，并伴随c-Jun n端磷酸化受损。在培养的角质形成细胞中，MEKK1对tgf - β和激活素激活JNK至关重要，但对tgf - α不起作用。mekk1驱动的JNK激活是肌动蛋白应激纤维形成、c-Jun磷酸化和细胞迁移所必需的。然而，MEKK1消融不会损害其他tgf - β /激活功能，如Smad4的核易位。这些结果确立了MEKK1- jnk级联在tgf - β和激活素信号传递中控制上皮细胞运动的特定作用，为MEKK1调控眼睑闭合提供了机制基础。该研究还表明，控制哺乳动物眼睑闭合和果蝇背部闭合的信号机制在进化上是保守的。
MEKK1-deficient mice show an eye open at birth phenotype caused by impairment in embryonic eyelid closure. MEK kinase 1 (MEKK1) is highly expressed in the growing tip of the eyelid epithelium, which displays loose cell-cell contacts and prominent F-actin fibers in wild-type mice, but compact cell contacts, lack of polymerized actin and a concomitant impairment in c-Jun N-terminal phosphorylation in MEKK1-deficient mice. In cultured keratinocytes, MEKK1 is essential for JNK activation by TGF-beta and activin, but not by TGF-alpha. MEKK1-driven JNK activation is required for actin stress fiber formation, c-Jun phosphorylation and cell migration. However, MEKK1 ablation does not impair other TGF-beta/activin functions, such as nuclear translocation of Smad4. These results establish a specific role for the MEKK1-JNK cascade in transmission of TGF-beta and activin signals that control epithelial cell movement, providing the mechanistic basis for the regulation of eyelid closure by MEKK1. This study also suggests that the signaling mechanisms that control eyelid closure in mammals and dorsal closure in Drosophila are evolutionarily conserved.