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Targeted deletion of the integrin beta4 signaling domain suppresses laminin-5-dependent nuclear entry of mitogen-activated protein kinases and NF-kappaB, causing defects in epidermal growth and migration.

The alpha6beta4 integrin-a laminin-5 receptor-mediates assembly of hemidesmosomes and recruitment of Shc and phosphoinositide 3-kinase through the unique cytoplasmic extension of beta4. Mice carrying a targeted deletion of the signaling domain of beta4 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 beta4 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 IkappaB in beta4 mutant cells adhering to laminin-5. Unexpectedly, however, ERK, JNK, and NF-kappaB remain in the cytoplasm in beta4 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 alpha6beta4 promotes keratinocyte proliferation and migration through its effect on NF-kappaB and P-JNK. These findings provide evidence that beta4 signaling promotes epidermal growth and wound healing through a previously unrecognized effect on nuclear translocation of NF-kappaB and mitogen-activated protein kinases.

Pubmed ID: 15988021

Authors

  • Nikolopoulos SN
  • Blaikie P
  • Yoshioka T
  • Guo W
  • Puri C
  • Tacchetti C
  • Giancotti FG

Journal

Molecular and cellular biology

Publication Data

July 30, 2005

Associated Grants

  • Agency: NCI NIH HHS, Id: F32 CA97886
  • Agency: PHS HHS, Id: GTF01018
  • Agency: NCI NIH HHS, Id: P30 CA08748
  • Agency: NCI NIH HHS, Id: R37 CA058976
  • Agency: NCI NIH HHS, Id: R37 CA58976

Mesh Terms

  • Active Transport, Cell Nucleus
  • Animals
  • Apoptosis
  • Cell Adhesion
  • Cell Adhesion Molecules
  • Cell Movement
  • Cell Nucleus
  • Epidermal Growth Factor
  • Epidermis
  • Gene Deletion
  • Gene Targeting
  • Integrin alpha6beta4
  • Integrin beta4
  • JNK Mitogen-Activated Protein Kinases
  • Keratinocytes
  • Mice
  • Mice, Mutant Strains
  • NF-kappa B
  • Protein Structure, Tertiary
  • Signal Transduction
  • Wound Healing