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.
Fujita
Yasuyuki
Y
Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany. fujita@mdc-berlin.de
Krause
Gerd
G
Scheffner
Martin
M
Zechner
Dietmar
D
Leddy
Hugo E Molina
HE
Behrens
Jürgen
J
Sommer
Thomas
T
Birchmeier
Walter
W
D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D004285:Dogs; D004705:Endocytosis / Q000502:physiology*; D008025:Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D013696:Temperature; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D011518:Proto-Oncogene Proteins; D025801:Ubiquitin; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D019061:src-Family Kinases; D008025:Ligases