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TWEAK promotes migration and invasion in MEFs through a mechanism dependent on ERKs activation and Fibulin 3

Celia Sequera1,2, Ana Vázquez-Carballo1,2, María Arechederra1,2

  • 1Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular II, Universidad Complutense de Madrid, Madrid, Spain.

Journal of Cellular Physiology
|April 7, 2017
PubMed

Insights

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) promotes fibroblast migration via extracellular signal-regulated kinases (ERKs) activation and Fibulin 3 reduction. This pathway is crucial for tissue repair mechanisms.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • TWEAK is known to regulate various cellular processes, including fibrosis and tumor cell migration.
  • p38α MAPK is implicated in promoting migration and invasion in cancer cells and fibroblasts.
  • The specific role of TWEAK in fibroblast migration and the involvement of p38α MAPK remained unclear.

Purpose of the Study:

  • To investigate whether TWEAK promotes migration in mouse embryonic fibroblasts (MEFs).
  • To determine the role of p38α MAPK in TWEAK-mediated fibroblast migration.
  • To elucidate the molecular mechanisms underlying TWEAK-induced fibroblast migration.

Main Methods:

  • Treatment of wild-type and p38α-deficient MEFs with TWEAK.
  • Analysis of MAPK pathway activation (ERK, Akt, p38α/β).
  • Assessment of Fibulin 3 levels.
  • Migration and invasion assays.
  • Pharmacological inhibition of ERKs.
  • Fibulin 3 knockdown experiments.

Main Results:

  • TWEAK activated ERKs, Akt, and p38α/β MAPKs in MEFs.
  • TWEAK reduced secreted Fibulin 3 levels.
  • TWEAK enhanced migration and invasion in both wild-type and p38α-deficient MEFs, indicating p38α independence.
  • ERK inhibition significantly reduced TWEAK-induced migration.
  • Fibulin 3 knockdown mimicked the TWEAK effect on migration.
  • ERKs activation and Fibulin 3 down-regulation mediate TWEAK's pro-migratory effect.

Conclusions:

  • TWEAK promotes fibroblast migration independently of p38α MAPK.
  • The pro-migratory effects of TWEAK are mediated by ERKs activation and Fibulin 3 down-regulation.
  • These findings reveal novel mechanisms for TWEAK in promoting tissue repair through fibroblast migration.
Keywords:
ERKsFibulin 3TWEAKmigration

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