Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 25, Issue 14, Pages 6090-6102Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.25.14.6090-6102.2005
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Funding
- NCI NIH HHS [F32 CA097886, P30 CA008748, R37 CA058976, P30 CA08748, F32 CA97886, R37 CA58976] Funding Source: Medline
- PHS HHS [GTF01018] Funding Source: Medline
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The alpha 6 beta 4 integrin-a laminin-5 receptor-mediates assembly of hemidesmosomes and recruitment of She and phosphoinositide 3-kinase through the unique cytoplasmic extension of beta 4. Mice carrying a targeted deletion of the signaling domain of beta 4 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 beta 4 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 I kappa B in beta 4 mutant cells adhering to laminin-5. Unexpectedly, however, ERK, JNK, and NF-kappa B remain in the cytoplasm in beta 4 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 alpha 6 beta 4 promotes keratinocyte proliferation and migration through its effect on NF-kappa B and P-JNK. These findings provide evidence that beta 4 signaling promotes epidermal growth and wound healing through a previously unrecognized effect on nuclear translocation of NF-kappa B and mitogen-activated protein kinases.
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