Selective changes in laminin adhesion and α6β4 integrin regulation are associated with the initial steps in keratinocyte maturation

Tamar Tennenbaum, Luowei Li, Adam J. Belanger, Luigi M. De Luca, Stuart H. Yuspa

Research output: Contribution to journalArticlepeer-review


In skin, the distribution of integrins is compartmentalized. Whereas the α6β4 integrin complex is polarized to the basal portion of proliferating cells in the basal layer juxtaposed to the basement membrane, α3β1 integrin receptors are localized on the cell surface surrounding basal and suprabasal cells, suggesting β1 integrins mediate both cell-matrix and cell-cell interactions. As initiation of maturation in skin is associated with the detachment of cells from the basement membrane, the early loss of α6β4, but not α3β1, integrin expression could be a determining factor in the transition from the proliferating to a differentiating keratinocyte. We have studied the regulation of adhesion potential and integrin expression during differentiation of mouse basal keratinocytes cultured in 0.05 mM Ca2+ medium and induced to differentiate in 0.12 mM Ca2+ medium. Within 12-24 h after elevation of Ca2+, a selective loss of the α6β4 integrin complex is associated with the induction of the spinous cell marker keratin 1. This early differentiation phenotype coincides with loss of cell attachment mediated by α6β4 to laminins 1 and 5 but not to fibronectin or collagen IV. Selective loss of attachment to laminin is also detected in spinous cells isolated from newborn epidermis in vivo. The loss of α6β4 protein expression is a consequence of transcriptional and posttranslational events, including reduction in mRNA transcripts, reduced synthesis of the α6 protein, and enhanced processing of the α6 and β4 chains as determined by Western blots and pulse-chase experiments in metabolically labeled keratinocytes. Selective processing of the β4 intracellular domain is detected before loss of β4 from the cell surface in basal keratinocytes, and this process is accelerated during differentiation. Whereas early keratinocyte maturation is linked to the selective loss of the α6β4 complex, loss of both β1 and β4 integrin mRNA and protein occurs as cells proceed to later stages in the differentiation program as induced by 0.5 mM Ca2+ or suspension culture. These conditions are characterized by accelerated expression of transglutaminase; reduced keratin 1 protein; loss of adhesion to fibronectin, laminin 1, laminin 5, and collagen IV; and rapid cell death. Contributing to the down-regulation of β1 integrins during terminal differentiation is a selective sensitivity of α3β1 but not α6β4 to down-regulation by transforming growth factors β1 and β2, factors that are also expressed differentially in normal skin. This study indicates that down-regulation of the α6β4 but not β1 integrins occurs during the initial steps of keratinocyte differentiation and is associated with detachment from the laminin matrix. Such changes could contribute an important signal to initiate the process of terminal keratinocyte differentiation.

Original languageEnglish (US)
Pages (from-to)615-628
Number of pages14
JournalCell Growth and Differentiation
Issue number5
StatePublished - Nov 7 1996
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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