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Engulfment protein GULP is regulator of transforming growth factor-β response in ovarian cells

Cheng-I J Ma1, Cyril Martin, Zhong Ma

  • 1Department of Medicine, McGill University, Montreal, Quebec H3A 1A1, Canada.

The Journal of Biological Chemistry
|March 28, 2012
PubMed

Insights

The adapter protein GULP enhances transforming growth factor beta (TGF-β) signaling in ovarian cells by retaining TGF-β in early endosomes, promoting growth inhibition and potentially serving as a therapeutic target.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Transforming growth factor beta (TGF-β) signaling is crucial for cell functions but its dysregulation contributes to cancer.
  • The TGF-β receptor V (also known as LRP1) mediates TGF-β-induced growth inhibition in Chinese hamster ovary (CHO) cells.
  • The LRP1 adapter protein GULP is involved in the internalization of LRP1 ligands.

Purpose of the Study:

  • To investigate the role of GULP as a novel regulator of TGF-β signaling in ovarian cells.
  • To elucidate the mechanism by which GULP influences TGF-β signaling.
  • To assess the therapeutic potential of GULP in ovarian cancer.

Main Methods:

  • Overexpression and knockdown of GULP in CHO cells.
  • Assessment of TGF-β-induced cell growth inhibition, migration, and invasion.
  • Analysis of SMAD3 phosphorylation.
  • GULP transfection into TGF-β-insensitive human ovarian adenocarcinoma cells (HEY).

Main Results:

  • Overexpression of GULP enhanced TGF-β-mediated growth inhibition, migration, and invasion in CHO cells.
  • GULP depletion impaired these TGF-β responses.
  • GULP prolonged TGF-β-induced SMAD3 phosphorylation by retaining TGF-β in signaling-competent early endosomes.
  • GULP reintroduction into HEY cells restored TGF-β responsiveness.

Conclusions:

  • GULP acts as a positive regulator of TGF-β signaling in ovarian cells.
  • GULP facilitates TGF-β-induced growth inhibition by maintaining receptor signaling.
  • GULP expression is low in human ovarian adenocarcinomas, suggesting its potential as a therapeutic target to restore TGF-β sensitivity.

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