Loss of alpha6 Integrins in Keratinocytes Leads to an Increase in TGFbeta and AP1 Signaling and in Expression of Differentiation Genes

J Cell Physiol. 2007 Aug;212(2):439-49. doi: 10.1002/jcp.21040.

Abstract

Mice lacking the alpha6 integrin chain die at birth with severe skin blistering. To further study the function of alpha6 integrin in skin, we generated conditionally immortalized cell lines from the epidermis of wild-type and alpha6 deficient mouse embryos. Mutant cells presented a decreased adhesion on laminin 5, the major component of the basement membrane in the skin, and on laminins 10/11 and 2. A DNA array analysis revealed alterations in the expression of extracellular matrix (ECM) components including laminin 5, cytoskeletal elements, but also membrane receptors like the hemidesmosomal components integrin beta4 and collagen XVII, or growth factors and signaling molecules of the TGFbeta, EGF, and Wnt pathways. Finally, an increase of several epidermal differentiation markers was observed in cells and tissue at the protein level. Further examination of the mutant tissue revealed alterations in the filaggrin signal. These differences may be linked to an upregulation of the TGFbeta and the Jun/Fos pathways in mutant keratinocytes. These results are in favor of a role for integrin alpha6beta4 in the maintenance of basal keratinocyte properties and epidermal homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cell Differentiation / genetics*
  • Cell Line
  • Cell Nucleus / metabolism
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Fetus / cytology
  • Fetus / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental*
  • Integrin alpha6 / genetics
  • Integrin alpha6 / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Keratinocytes / metabolism*
  • Laminin / metabolism
  • Mice
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Signal Transduction / genetics*
  • Transcription Factor AP-1 / metabolism*
  • Transforming Growth Factor beta / metabolism*

Substances

  • Cell Adhesion Molecules
  • Extracellular Matrix Proteins
  • Integrin alpha6
  • Intracellular Signaling Peptides and Proteins
  • Laminin
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Receptors, Cell Surface
  • Transcription Factor AP-1
  • Transforming Growth Factor beta
  • kalinin
  • laminin 10