α3β1 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, C. Michael DiPersio

Research output: Contribution to journalArticlepeer-review

Abstract

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 α3β1 and α6β4 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 α3 integrin knockout mice to reveal a critical role for α3β1 in protecting keratinocytes from apoptosis upon serum withdrawal. We show that α3β1-mediated adhesion to laminin-5 extracellular matrix inhibits proteolytic activation of caspase-3 and TUNEL-staining, both hallmarks of apoptosis. We also show that α3β1-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. α6β4-mediated adhesion to laminin-5 only partially protects cells from apoptosis in the absence of α3β1, and α 6β4 is not necessary for cell survival in the presence of α 3β1. These results suggest that α3β1 is necessary and sufficient for maximal keratinocyte survival on laminin-5. We propose a model to address the potential importance of α3β1-mediated survival for migrating keratinocytes at the leading edge of a cutaneous wound.

Original languageEnglish (US)
Pages (from-to)4043-4054
Number of pages12
JournalJournal of cell science
Volume117
Issue number18
DOIs
StatePublished - Aug 15 2004

Keywords

  • Anoikis
  • Apoptosis
  • ERK
  • Keratinocyte
  • α3β1 integrin

ASJC Scopus subject areas

  • Cell Biology

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