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JCS ePress online publication date 27 Jul 2004
doi: 10.1242/jcs.01277

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Research Article

{alpha}3{beta}1 integrin promotes keratinocyte cell survival through activation of a MEK/ERK signaling pathway


Asha Manohar, Swati Ghosh Shome, John Lamar, Lee Stirling, Vandana Iyer, Kevin Pumiglia, and C. Michael DiPersio*
* Author for correspondence (e-mail: dipersm{at}mail.amc.edu)

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 {alpha}3{beta}1 and {alpha}6{beta}4 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 {alpha}3 integrin knockout mice to reveal a critical role for {alpha}3{beta}1 in protecting keratinocytes from apoptosis upon serum withdrawal. We show that {alpha}3{beta}1-mediated adhesion to laminin-5 extracellular matrix inhibits proteolytic activation of caspase-3 and TUNEL-staining, both hallmarks of apoptosis. We also show that {alpha}3{beta}1-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. {alpha}6{beta}4-mediated adhesion to laminin-5 only partially protects cells from apoptosis in the absence of {alpha}3{beta}1, and {alpha}6{beta}4 is not necessary for cell survival in the presence of {alpha}3{beta}1. These results suggest that {alpha}3{beta}1 is necessary and sufficient for maximal keratinocyte survival on laminin-5. We propose a model to address the potential importance of {alpha}3{beta}1-mediated survival for migrating keratinocytes at the leading edge of a cutaneous wound.
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