Metalloproteinase-mediated, context-dependent function of amphiregulin and hb-egf in human keratinocytes and skin

Stefan W. Stoll, Jessica L. Johnson, Ajay Bhasin, Andrew Johnston, Johann E. Gudjonsson, Laure Rittié, James T. Elder

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Human keratinocytes (KCs) express multiple EGF receptor (EGFR) ligands; however, their functions in specific cellular contexts remain largely undefined. To address this issue, first we measured mRNA and protein levels for multiple EGFR ligands in KCs and skin. Amphiregulin (AREG) was by far the most abundant EGFR ligand in cultured KCs, with >19 times more mRNA and >7.5 times more shed protein than any other family member. EGFR ligand expression in normal skin was low (<8% of RPLP0/36B4); however, HB-EGF and AREG mRNAs were strongly induced in human skin organ culture. KC migration in scratch wound assays was highly metalloproteinase (MP)-and EGFR dependent, and was markedly inhibited by EGFR ligand antibodies. However, lentivirus-mediated expression of soluble HB-EGF, but not soluble AREG, strongly enhanced KC migration, even in the presence of MP inhibitors. Lysophosphatidic acid (LPA)-induced ERK phosphorylation was also strongly EGFR and MP dependent and markedly inhibited by neutralization of HB-EGF. In contrast, autocrine KC proliferation and ERK phosphorylation were selectively blocked by neutralization of AREG. These data show that distinct EGFR ligands stimulate KC behavior in different cellular contexts, and in an MP-dependent fashion.

Original languageEnglish (US)
Pages (from-to)295-304
Number of pages10
JournalJournal of Investigative Dermatology
Volume130
Issue number1
DOIs
StatePublished - Jan 1 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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