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Kindlin-1 protects cells from oxidative damage through activation of ERK signalling

Hila Emmert1, Hitesh Patel1, Valerie G Brunton1

  • 1Edinburgh Cancer Research UK Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.

Free Radical Biology & Medicine
|May 15, 2017
PubMed

Insights

Loss of Kindlin-1 (a protein crucial for cell adhesion) increases sensitivity to oxidative stress and DNA damage in skin cells. This deficiency impairs ERK signaling, contributing to Kindler Syndrome

Area of Science:

  • Cell Biology
  • Dermatology
  • Molecular Biology

Background:

  • Kindlin-1 is an adaptor protein at cell-extracellular matrix adhesions, essential for integrin activation.
  • Loss-of-function mutations in FERMT1 (encoding Kindlin-1) cause Kindler Syndrome (KS), a disorder marked by skin blistering, photosensitivity, and SCC predisposition.

Purpose of the Study:

  • To investigate the role of Kindlin-1 in cellular response to oxidative stress.
  • To elucidate the molecular mechanisms linking Kindlin-1 deficiency to increased susceptibility to DNA damage and photosensitivity in Kindler Syndrome.

Main Methods:

  • Assessing reactive oxygen species (ROS) levels, cell viability, and DNA damage in Kindlin-1 deficient and expressing keratinocytes and SCC cells.
  • Evaluating the impact of hydrogen peroxide (H2O2) and UVA irradiation on these cells.
  • Analyzing the involvement of ERK signaling pathway activation in response to oxidative stress.
  • Investigating the dependence of these processes on Kindlin-1's integrin-binding ability.

Main Results:

  • Kindlin-1 deficient cells exhibit elevated ROS levels, reduced viability, and increased DNA damage upon exposure to oxidative stressors (H2O2, UVA).
  • Kindlin-1 is essential for full ERK signaling activation following oxidative damage; ERK activation confers protection against DNA damage.
  • Kindlin-1's ability to bind integrins is critical for its role in ERK activation and protection from oxidative stress-induced DNA damage.

Conclusions:

  • Loss of Kindlin-1 disrupts cellular oxidative balance, making cells more vulnerable to ROS and DNA damage.
  • Kindlin-1-mediated ERK signaling activation is a key factor protecting keratinocytes from oxidative damage, explaining the increased photosensitivity observed in Kindler Syndrome patients.
Keywords:
ERKIntegrinKindlin-1ROSUV

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