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 Journal Article
| Authors: | Nikolopoulos, S. N.; Blaikie, P.; Yoshioka, T.; Guo, W.; Puri, C.; Tacchetti, C.; Giancotti, F. G. |
| Article Title: | 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 |
| 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. Copyright © 2005, American Society for Microbiology. All Rights Reserved. |
| Keywords: | signal transduction; epidermal growth factor; mitogen activated protein kinase; controlled study; protein phosphorylation; gene deletion; nonhuman; protein domain; cell proliferation; animal cell; mouse; animals; mice; gene targeting; apoptosis; cell growth; basement membrane; epidermis; stress activated protein kinase; protein degradation; animal experiment; animal model; mice, mutant strains; immunoglobulin enhancer binding protein; keratinocyte; wound healing; nf-kappa b; newborn; protein transport; cell migration; cell movement; cellular distribution; cytoplasm; active transport, cell nucleus; cell adhesion molecules; protein structure, tertiary; cell nucleus; cell adhesion; keratinocytes; matrix protein; integrin beta4; fibronectin; jnk mitogen-activated protein kinases; i kappa b; kalinin; alpha6beta4 integrin; hemidesmosome; hypoplasia; integrin alpha6beta4 |
| Journal Title: | Molecular and Cellular Biology |
| Volume: | 25 |
| Issue: | 14 |
| ISSN: | 0270-7306 |
| Publisher: | American Society for Microbiology |
| Date Published: | 2005-07-01 |
| Start Page: | 6090 |
| End Page: | 6102 |
| Language: | English |
| DOI: | 10.1128/mcb.25.14.6090-6102.2005 |
| PUBMED: | 15988021 |
| PROVIDER: | scopus |
| PMCID: | PMC1168825 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 65" - "Export Date: 24 October 2012" - "CODEN: MCEBD" - "Source: Scopus" |
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