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Regulation of folate receptor internalization by protein kinase C alpha

Hala Elnakat1, Mesfin Gonit, Marcela D'Alincourt Salazar

  • 1Department of Biochemistry and Cancer Biology, Medical University of Ohio, 3000 Arlington Avenue, Toledo, Ohio 43614, USA.

Biochemistry
|July 31, 2009
PubMed

Insights

Protein kinase C alpha (PKCalpha) regulates folate receptor (FR) recycling. Activated PKCalpha inhibits FR internalization, potentially enhancing targeted drug delivery to tumors.

Area of Science:

  • Cell biology
  • Molecular pharmacology
  • Cancer therapeutics

Background:

  • The folate receptor (FR) is crucial for targeted drug delivery to tumors.
  • FR internalization mechanisms are not fully understood.
  • FR recycles via a Cdc42-dependent pathway.

Purpose of the Study:

  • To elucidate the molecular mechanisms regulating folate receptor (FR) internalization and recycling.
  • To identify the role of Protein Kinase C (PKC) in FR trafficking.
  • To explore potential therapeutic strategies for enhancing FR-mediated drug delivery.

Main Methods:

  • Investigated FR recycling using biochemical and cell imaging techniques.
  • Utilized PKC activators (phorbol ester) and inhibitors.
  • Examined the interaction of PKCalpha with FR in membrane microdomains.
  • Assessed the role of Cdc42 and annexin II in FR internalization.

Main Results:

  • Identified Protein Kinase C alpha (PKCalpha) as the mediator of phorbol ester's effect on FR recycling.
  • Demonstrated that activated PKCalpha, with RACK1, inhibits FR internalization at the cell surface.
  • Showed that Cdc42 activation state remains unchanged during this process.
  • Confirmed annexin II as a required substrate for FR internalization.

Conclusions:

  • Clarified a novel molecular mechanism regulating FR recycling via PKCalpha.
  • PKCalpha activation inhibits FR internalization, suggesting a method to increase cell surface FR.
  • This mechanism offers potential for optimizing FR-targeted drug delivery strategies.

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