Journal
EMBO JOURNAL
Volume 22, Issue 17, Pages 4443-4454Publisher
OXFORD UNIV PRESS
DOI: 10.1093/emboj/cdg440
Keywords
actin stress fiber; embryonic eyelid closure; epithelial cell migration; MEKK1-JNK pathway; TGF-beta; activin signaling
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Funding
- NEI NIH HHS [EY 11845, EY 05129, R01 EY005129, EY 12486, R01 EY015227, EY 13755] Funding Source: Medline
- NIEHS NIH HHS [ES04151, R01 ES006376, R37 ES004151, ES06376, P30 ES06096] Funding Source: Medline
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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.
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