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

• Published in: Molecular and cellular biology 2005-07, Vol.25 (14), p.6090
• Main Authors: Nikolopoulos, Sotiris N, Blaikie, Pamela, Yoshioka, Toshiaki, Guo, Wenjun, Puri, Claudia, Tacchetti, Carlo, Giancotti, Filippo G
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Animals; Apoptosis; Cell Adhesion; Cell Adhesion Molecules - antagonists & inhibitors; Cell Adhesion Molecules - physiology; Cell Movement; Cell Nucleus - metabolism; Epidermal Cells; Epidermal Growth Factor - pharmacology; Epidermis - growth & development; Gene Deletion; Gene Targeting; Integrin alpha6beta4 - genetics; Integrin alpha6beta4 - physiology; Integrin beta4 - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; Kalinin; Keratinocytes - drug effects; Keratinocytes - metabolism; Mice; Mice, Mutant Strains; NF-kappa B - metabolism; Protein Structure, Tertiary; Signal Transduction; Wound Healing - genetics; Wound Healing - physiology
• ISSN: 0270-7306

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.