Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2

Genes Dev. 2015 Jan 15;29(2):144-56. doi: 10.1101/gad.249748.114. Epub 2014 Dec 29.


Altered epidermal differentiation characterizes numerous skin diseases affecting >25% of the human population. Here we identified Fra-2/AP-1 as a key regulator of terminal epidermal differentiation. Epithelial-restricted, ectopic expression of Fra-2 induced expression of epidermal differentiation genes located within the epidermal differentiation complex (EDC). Moreover, in a papilloma-prone background, a reduced tumor burden was observed due to precocious keratinocyte differentiation by Fra-2 expression. Importantly, loss of Fra-2 in suprabasal keratinocytes is sufficient to cause skin barrier defects due to reduced expression of differentiation genes. Mechanistically, Fra-2 binds and transcriptionally regulates EDC gene promoters, which are co-occupied by the transcriptional repressor Ezh2. Fra-2 remains transcriptionally inactive in nondifferentiated keratinocytes, where it was found monomethylated and dimethylated on Lys104 and interacted with Ezh2. Upon keratinocyte differentiation, Fra-2 is C-terminally phosphorylated on Ser320 and Thr322 by ERK1/2, leading to transcriptional activation. Thus, the induction of epidermal differentiation by Fra-2 is controlled by a dual mechanism involving Ezh2-dependent methylation and activation by ERK1/2-dependent phosphorylation.

Keywords: ERK1/2; Ezh2/PRC2; Fra-2/AP-1; epidermal differentiation complex; nonhistone substrate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cells, Cultured
  • Embryo, Mammalian
  • Enhancer of Zeste Homolog 2 Protein
  • Fos-Related Antigen-2 / metabolism*
  • Gene Expression Regulation, Developmental
  • Keratinocytes / cytology*
  • Lysine / metabolism
  • Methylation
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Phosphorylation
  • Polycomb Repressive Complex 2 / metabolism*
  • Transcription Factor AP-1 / metabolism*


  • Fos-Related Antigen-2
  • Fosl2 protein, mouse
  • Transcription Factor AP-1
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Polycomb Repressive Complex 2
  • Mitogen-Activated Protein Kinase 1
  • Lysine