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Molecular and Cellular Biology, July 2005, p. 6090-6102, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.6090-6102.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Targeted Deletion of the Integrin ß4 Signaling Domain Suppresses Laminin-5-Dependent Nuclear Entry of Mitogen-Activated Protein Kinases and NF-B, Causing Defects in Epidermal Growth and Migration

Sotiris N. Nikolopoulos,^1, Pamela Blaikie,^1, Toshiaki Yoshioka,¹ Wenjun Guo,¹ Claudia Puri,² Carlo Tacchetti,² and Filippo G. Giancotti^1*

Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York,¹ IFOM Center of Cell Oncology and Ultrastructure, Department of Experimental Medicine, University of Genova, Genoa, Italy²

Received 10 November 2004/ Returned for modification 20 December 2004/ Accepted 28 April 2005

The 6ß4 integrin—a laminin-5 receptor—mediates assembly of hemidesmosomes and recruitment of Shc and phosphoinositide 3-kinase through the unique cytoplasmic extension of ß4. Mice carrying a targeted deletion of the signaling domain of ß4 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 ß4 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 IB in ß4 mutant cells adhering to laminin-5. Unexpectedly, however, ERK, JNK, and NF-B remain in the cytoplasm in ß4 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 6ß4 promotes keratinocyte proliferation and migration through its effect on NF-B and P-JNK. These findings provide evidence that ß4 signaling promotes epidermal growth and wound healing through a previously unrecognized effect on nuclear translocation of NF-B and mitogen-activated protein kinases.

S.N.N. and P.B. contributed equally.

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