A role for MEK kinase 1 in TGF-beta/activin-induced epithelium movement and embryonic eyelid closure

EMBO J. 2003 Sep 1;22(17):4443-54. doi: 10.1093/emboj/cdg440.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / metabolism
  • Activins / physiology
  • Animals
  • Base Sequence
  • Biological Evolution
  • Cell Movement / physiology
  • DNA / genetics
  • Drosophila / embryology
  • Enzyme Activation
  • Epithelium / abnormalities
  • Epithelium / embryology
  • Epithelium / metabolism
  • Eyelids / abnormalities
  • Eyelids / embryology*
  • Eyelids / metabolism
  • JNK Mitogen-Activated Protein Kinases
  • Keratinocytes / physiology
  • MAP Kinase Kinase Kinase 1*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Signal Transduction
  • Transforming Growth Factor beta / physiology


  • Actins
  • Transforming Growth Factor beta
  • Activins
  • DNA
  • Protein-Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • Map3k1 protein, mouse