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Protein kinaseCdelta-calmodulin crosstalk regulates epidermal growth factor receptor exit from early endosomes

Anna Lladó1, Francesc Tebar, Maria Calvo

  • 1Departament de Biologia Cellular, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain.

Molecular Biology of the Cell
|September 3, 2004
PubMed

Insights

Calmodulin antagonist W13 blocks epidermal growth factor receptor (EGFR) trafficking. Protein Kinase C delta inhibition specifically releases this blockage, restoring EGFR transport from early endosomes.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Endocytosis

Background:

  • Calmodulin antagonist W13 impacts epidermal growth factor receptor (EGFR) trafficking and mitogen-activated protein kinase (MAPK) signaling.
  • Understanding the molecular mechanisms regulating EGFR trafficking is crucial for cellular signaling research.

Purpose of the Study:

  • To investigate the role of Protein Kinase C (PKC) in calmodulin-mediated regulation of EGFR and transferrin trafficking.
  • To identify specific PKC isoforms involved in the W13-induced blockage of EGFR transport.

Main Methods:

  • Inhibition of calmodulin using W13.
  • Treatment with various Protein Kinase C (PKC) inhibitors (rottlerin, Gö 6976) and dominant-negative PKC isoforms.
  • Down-modulation of PKC isoforms using small interfering RNA (siRNA).
  • Analysis of epidermal growth factor receptor (EGFR) and transferrin trafficking.
  • Assessment of brefeldin A-induced tubulation and dextran-fluorescein isothiocyanate transport.

Main Results:

  • PKC inhibition restored EGFR and transferrin trafficking through the recycling compartment, but not to the degradative pathway.
  • Inhibition or down-modulation of PKCdelta specifically released the W13-induced blockage of EGFR trafficking from early endosomes.
  • Inhibition of conventional PKCs or expression of dominant-negative PKClambda, zeta, or epsilon did not rescue W13 effects.
  • W13 and rottlerin treatment recovered brefeldin A tubulation and transport to the late endocytic compartment.

Conclusions:

  • A specific interplay exists between calmodulin and PKCdelta in regulating early endocytic compartment morphology and trafficking.
  • PKCdelta plays a critical role in the calmodulin-mediated regulation of EGFR trafficking.
  • These findings provide new insights into the complex pathways governing endosomal transport.

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