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First published online 27 July 2004
doi: 10.1242/jcs.01277
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Research Article |
3ß1 integrin promotes keratinocyte cell survival through activation of a MEK/ERK signaling pathway
Center for Cell Biology and Cancer Research, Albany Medical College, MC-165, 47 New Scotland Avenue, Albany, New York, NY 12208, USA
Author for correspondence (e-mail: dipersm{at}mail.amc.edu)
Accepted 20 April 2004
Inadequate or inappropriate adhesion of epithelial cells to extracellular matrix leads to a form of apoptosis known as anoikis. During various tissue remodelling events, such as wound healing or carcinoma invasion, changes in the physical properties, and/or composition of the extracellular matrix, can lead to anoikis of epithelial cells that lack appropriate receptor-matrix interactions. Laminin-5 is the major ligand for keratinocyte adhesion in the epidermis, and it also promotes keratinocyte survival in vivo and in vitro. Integrins 
3ß1 and 6ß4 are the major receptors for laminin-5; however, specific roles for these integrins in keratinocyte survival have not been determined. In the current study, we exploited keratinocyte cell lines derived from wild-type or 3 integrin knockout mice to reveal a critical role for 3ß1 in protecting keratinocytes from apoptosis upon serum withdrawal. We show that 3ß1-mediated adhesion to laminin-5 extracellular matrix inhibits proteolytic activation of caspase-3 and TUNEL-staining, both hallmarks of apoptosis. We also show that 3ß1-mediated adhesion activates focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), and that inhibition of either FAK or ERK signaling leads to apoptosis of keratinocytes attached to laminin-5. 6ß4-mediated adhesion to laminin-5 only partially protects cells from apoptosis in the absence of 3ß1, and 6ß4 is not necessary for cell survival in the presence of 3ß1. These results suggest that 3ß1 is necessary and sufficient for maximal keratinocyte survival on laminin-5. We propose a model to address the potential importance of 3ß1-mediated survival for migrating keratinocytes at the leading edge of a cutaneous wound.
Key words: 3ß1 integrin, Keratinocyte, Apoptosis, Anoikis, ERK
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