title: Extracellular epimorphin modulates epidermal differentiation signals mediated by epidermal growth factor receptor.
abstract: BACKGROUND
  The epidermal stratification/differentiation program is initiated in keratinocytes by a basement membrane-detachment cue and subsequently controlled by spatially and temporally regulated signaling molecules. The vital signals for the developmental behavior of the epidermis include those mediated by epidermal growth factor receptor (EGFR); however, regulatory elements responsible for activation have not yet been fully elucidated.
  
  
  OBJECTIVE
  The objectives of this study were (1) to assess the effects of EGFR activation on epidermal differentiation, (2) to study the effects of epimorphin on the level of EGFR signaling degree dependent on matrix engagement, and (3) to address the impact of epimorphin modulation on EGFR-driven epidermal differentiation in a three-dimensional (3D) organotypic skin model.
  
  
  METHODS
  We constructed skin-equivalent models with a well-stratified differentiated epidermis and utilized them to evaluate the epidermal behaviors.
  
  
  RESULTS
  Extracellularly secreted epimorphin was identified as a strong candidate for signaling pathway involvement. In a 3D epidermis model, EGF stimulation was sufficient for epidermal stratification. However, overactivation of EGFR led to irregular multicellular arrangements with an abnormal differentiation profile, which appeared to be reorganized back to the normal epidermal phenotype by extracellular epimorphin. Extracellular epimorphin interestingly attenuated EGF-stimulated EGFR phosphorylation, cell growth, and migration in adherent cells. In contrast to the results of adhesion culture, extracellular epimorphin reinforced EGFR activation in suspended cells.
  
  
  CONCLUSIONS
  These results demonstrate that epimorphin modulates the signaling pathways mediated by EGFR for epidermal tissue organization.
authors.affiliation: Department of Bioscience, School of Science and Engineering, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337, Japan. okugawa_youji@bathclin.co.jp.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Okugawa
authors.forename: Yohei
authors.initials: Y
authors.lastname: Hirai
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism*; D002448:Cell Adhesion; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D051379:Mice; D041681:NIH 3T3 Cells; D010641:Phenotype; D010766:Phosphorylation; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D050827:Syntaxin 1 / Q000378:metabolism*
chemical_list: C074558:STX2 protein, human; D050827:Syntaxin 1; D003094:Collagen; D066246:ErbB Receptors