Cited by 50HER2/EGFR in Cancer ResearchWound Healing and TreatmentsProtease and Inhibitor Mechanisms

Metalloproteinase-mediated, context-dependent function of amphiregulin and HB-EGF in human keratinocytes and skin

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Stoll, Stefan W., Johnson, Jessica L., Bhasin, Ajay, Johnston, Andrew, Gudjonsson, Johann E., Rittié, Laure, Elder, James T.·2010·Journal of Investigative Dermatology

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 per thousand 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.

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Authors
Stoll, S. W., Johnson, J. L., Bhasin, A., Johnston, A., Gudjonsson, J. E., Rittié, L., & Elder, J. T.
Affiliations
University of Michigan (US)
Corresponding author
Stoll, Stefan W.
Venue
Journal of Investigative Dermatology
Publisher
Elsevier BV
Published
2010-01
Volume
130
Issue
1
Pages
295-304
ISSN
0022-202X (ISSN-L)
OpenAlex
W2030005349
Cited by
50
References
75
Citations by year
2026: 3 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 5 · 2014: 9 · 2012: 4
FWCI
2.33
Type
journal article
Language
en
Open access
Locations
  • Journal of Investigative Dermatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • Dermatology Foundation
  • National Institutes of Health
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R03AR049420, R01AR052889, K01AR050462)
Topics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords
amphiregulin, HB-EGF, EGFR ligands, metalloproteinases, keratinocytes, keratinocyte migration, skin organ culture, lysophosphatidic acid, ERK1/2 phosphorylation
MeSH terms
Cell Division, Cell Movement, Cells, Cultured, Glycoproteins, Humans, Ligands, Lipopolysaccharides, Organ Culture Techniques, Phosphorylation, RNA, Messenger, Skin, Signal Transduction, Keratinocytes, Lentivirus, Autocrine Communication, Intercellular Signaling Peptides and Proteins, Metalloproteases, Extracellular Signal-Regulated MAP Kinases, ErbB Receptors, EGF Family of Proteins, Heparin-binding EGF-like Growth Factor, Amphiregulin

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