Targeted deletion of the integrin β4 signaling domain suppresses laminin-5-dependent nuclear entry of mitogen-activated protein kinases and NF-κB, causing defects in epidermal growth and migration

Sotiris N. Nikolopoulos, Pamela Blaikie, Toshiaki Yoshioka, Wenjun Guo, Claudia Puri, Carlo Tacchetti, Filippo G. Giancotti

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

The α6β4 integrin-a laminin-5 receptor-mediates assembly of hemidesmosomes and recruitment of Shc and phosphoinositide 3-kinase through the unique cytoplasmic extension of β4. Mice carrying a targeted deletion of the signaling domain of β4 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 β4 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 IκB in β4 mutant cells adhering to laminin-5. Unexpectedly, however, ERK, JNK, and NF-κB remain in the cytoplasm in β4 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 α6β4 promotes keratinocyte proliferation and migration through its effect on NF-κB and P-JNK. These findings provide evidence that β4 signaling promotes epidermal growth and wound healing through a previously unrecognized effect on nuclear translocation of NF-κB and mitogen-activated protein kinases.

Original languageEnglish (US)
Pages (from-to)6090-6102
Number of pages13
JournalMolecular and cellular biology
Volume25
Issue number14
DOIs
StatePublished - Jul 1 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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