Alpha 3 beta 1 integrin promotes keratinocyte cell survival through activation of a MEK/ ERK signaling pathway.
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 beta1- 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.[1]References
- Alpha 3 beta 1 integrin promotes keratinocyte cell survival through activation of a MEK/ERK signaling pathway. Manohar, A., Shome, S.G., Lamar, J., Stirling, L., Iyer, V., Pumiglia, K., DiPersio, C.M. J. Cell. Sci. (2004) [Pubmed]
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