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Phosphorylation of claudin-4 by PKCepsilon regulates tight junction barrier function in ovarian cancer cells

Theresa D'Souza1, Fred E Indig, Patrice J Morin

  • 1Laboratory of Cellular and Molecular Biology, National Institute on Aging, Baltimore, MD 21224, USA.

Experimental Cell Research
|August 7, 2007
PubMed

Insights

Protein kinase C (PKC) phosphorylates claudin-4 in ovarian cancer cells, disrupting tight junction barrier function. PKCepsilon may mediate this effect, offering insights into ovarian cancer progression and normal epithelial cell regulation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Claudin proteins are crucial for tight junction (TJ) formation and maintenance.
  • Claudin-4 is overexpressed in ovarian cancer, potentially influencing survival and invasion.
  • Mechanisms regulating claudin-4 in ovarian cancer remain largely unknown.

Purpose of the Study:

  • To investigate the molecular mechanisms regulating claudin-4 activity in ovarian cancer.
  • To determine the role of protein kinase C (PKC) in claudin-4 phosphorylation and function.
  • To identify specific PKC isoforms involved in claudin-4 regulation in ovarian cancer cells.

Main Methods:

  • Phosphorylation site analysis of claudin-4.
  • Overexpression of wild-type and mutant claudin-4.
  • PKC activation and inhibition studies.
  • Small interfering RNA (siRNA) knockdown of PKC isoforms.
  • Immunofluorescence microscopy for protein co-localization.

Main Results:

  • Claudin-4 is phosphorylated by PKC at Thr189 and Ser194 in ovarian cancer cells.
  • Overexpression of a phosphorylated claudin-4 mimic disrupts TJ barrier function.
  • PKC activation decreases TJ strength and alters claudin-4 localization.
  • PKCepsilon is implicated in TPA-mediated claudin-4 phosphorylation and TJ weakening.
  • Claudin-4 and PKCepsilon show co-localization at TJs.

Conclusions:

  • PKC-mediated phosphorylation of claudin-4 disrupts TJ barrier function in ovarian cancer.
  • PKCepsilon plays a significant role in regulating claudin-4 activity and TJ integrity.
  • This regulatory mechanism may be relevant to both ovarian cancer progression and normal epithelial cell physiology.

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