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Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex

Yasuyuki Fujita1, Gerd Krause, Martin Scheffner

  • 1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany. fujita@mdc-berlin.de

Nature Cell Biology
|February 12, 2002
PubMed

Insights

Researchers discovered Hakai, an E3 ubiquitin ligase that targets E-cadherin for degradation. Hakai disrupts epithelial cell adhesion and motility, potentially influencing cancer metastasis and development.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Tyrosine kinases regulate E-cadherin function in epithelial cells.
  • E-cadherin phosphorylation and ubiquitination lead to its endocytosis.
  • Disruption of cell-cell adhesion is crucial in development and metastasis.

Purpose of the Study:

  • To identify proteins that bind to and regulate E-cadherin.
  • To characterize the function of the identified E-cadherin-binding protein, Hakai.
  • To investigate Hakai's role in cell adhesion, endocytosis, and motility.

Main Methods:

  • Modified yeast two-hybrid system for protein interaction screening.
  • Biochemical assays to confirm E3 ubiquitin ligase activity.
  • Cell-based assays to assess effects on cell-cell contacts, E-cadherin endocytosis, and cell motility.

Main Results:

  • Hakai was identified as an E-cadherin binding protein and an E3 ubiquitin ligase.
  • Hakai interacts with E-cadherin in a tyrosine phosphorylation-dependent manner.
  • Hakai expression leads to E-cadherin ubiquitination, increased endocytosis, disrupted cell-cell contacts, and enhanced cell motility.

Conclusions:

  • Hakai modulates cell adhesion through dynamic recycling of E-cadherin.
  • Hakai's function suggests a role in regulating epithelial-mesenchymal transitions.
  • Hakai may be involved in developmental processes and cancer metastasis.

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