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Isolation and Culture of Primary Mouse Keratinocytes from Neonatal and Adult Mouse Skin
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iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function

Matthew A Brooke1, Sarah L Etheridge1, Nihal Kaplan2

  • 1Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Human Molecular Genetics
|March 20, 2014
PubMed

Insights

Mutations in iRHOM2 protein increase ADAM17 activity in skin cells, leading to elevated growth factor shedding and a wound-healing-like phenotype. This discovery offers new insights into skin repair and inflammation pathways.

Area of Science:

  • Cell Biology
  • Dermatology
  • Genetics

Background:

  • iRHOM2, a catalytically inactive Rhomboid family member, regulates ADAM17 (TACE) maturation in macrophages.
  • Dominant iRHOM2 mutations cause tylosis with oesophageal cancer (TOC), a cancer-susceptibility syndrome, indicating a role in epithelial cells.

Purpose of the Study:

  • To investigate the function of iRHOM2 mutations in epithelial cells, specifically in the context of TOC.
  • To elucidate the molecular mechanisms linking iRHOM2 mutations to cancer susceptibility and skin phenotypes.

Main Methods:

  • Analysis of tissues from TOC patients.
  • Assessment of ADAM17 maturation and activity in epidermal keratinocytes.
  • Evaluation of ADAM17 substrate shedding, EGFR activity, desmosome processing, and transglutaminase activity.

Main Results:

  • TOC-associated iRHOM2 mutations increase ADAM17 maturation and activity in epidermal keratinocytes.
  • Upregulated shedding of ADAM17 substrates, including EGF-family growth factors and pro-inflammatory cytokines, was observed.
  • Increased EGFR activity, altered desmosome processing, heightened transglutaminase activity, and enhanced resistance to Staphylococcal infection were noted in TOC keratinocytes.

Conclusions:

  • iRHOM2 mutations promote a constitutive wound-healing-like phenotype in the epidermis.
  • This study reveals a novel pathway involving iRHOM2, ADAM17, and epidermal homeostasis, with implications for skin repair, regeneration, and inflammation.

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