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Dysregulation of Ack1 inhibits down-regulation of the EGF receptor

Lene Melsaether Grøvdal1, Lene E Johannessen, Marianne Skeie Rødland

  • 1University of Oslo, Institute of Pathology, Rikshospitalet HF, Oslo, Norway.

Experimental Cell Research
|February 12, 2008
PubMed

Insights

Protein tyrosine kinase Ack1 plays a role in epidermal growth factor receptor (EGFR) desensitization. Ack1 influences EGFR internalization and recycling, suggesting its involvement in cancer progression.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Protein tyrosine kinase Ack1 is implicated in cancer when overexpressed.
  • Ack1 has proposed roles in clathrin-mediated endocytosis and epidermal growth factor receptor (EGFR) downregulation.

Purpose of the Study:

  • To investigate the intracellular localization of overexpressed Ack1.
  • To elucidate Ack1's role in EGFR endocytosis, trafficking, and desensitization.

Main Methods:

  • Studied intracellular localization of overexpressed Ack1 via co-localization with EGFR.
  • Utilized EGF-induced endocytosis assays in cells with varying Ack1 expression levels.
  • Employed siRNA to knock down Ack1 and assessed (125)I-EGF and (125)I-transferrin internalization, recycling, and degradation.

Main Results:

  • Overexpressed Ack1 co-localizes with EGFR in early endosomes during EGF-induced endocytosis.
  • Ack1 overexpression retains EGFR at the early endosome limiting membrane, inhibiting sorting into multivesicular bodies.
  • Ack1 downregulation reduces (125)I-EGF internalization rate.
  • Ack1 knockdown increases (125)I-EGF recycling and decreases its degradation.

Conclusions:

  • Ack1 is involved in the early stages of EGFR desensitization.
  • Ack1 influences EGFR trafficking, affecting its internalization, recycling, and degradation pathways.

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