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

In epithelial cells, tyrosine kinases induce the tyrosine phosphorylation and ubiquitination of the E-cadherin complex, which induces endocytosis of E-cadherin. With a modified yeast 2-hybrid system, we isolated Hakai, an E-cadherin binding protein, which we have identified as an E3 ubiquitin-ligase. Hakai contains SH2, RING, zinc-finger and proline-rich domains, and interacts with E-cadherin in a tyrosine phosphorylation-dependent manner, inducing ubiquitination of the E-cadherin complex. Expression of Hakai in epithelial cells disrupts cell--cell contacts and enhances endocytosis of E-cadherin and cell motility. Through dynamic recycling of E-cadherin, Hakai can thus modulate cell adhesion, and could participate in the regulation of epithelial--mesenchymal transitions in development or metastasis.

Pubmed ID: 11836526


  • Fujita Y
  • Krause G
  • Scheffner M
  • Zechner D
  • Leddy HE
  • Behrens J
  • Sommer T
  • Birchmeier W


Nature cell biology

Publication Data

March 4, 2002

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Cadherins
  • Cell Adhesion
  • Cell Line
  • Cell Movement
  • Dogs
  • Endocytosis
  • Ligases
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Protein Binding
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-cbl
  • Temperature
  • Two-Hybrid System Techniques
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • src-Family Kinases