InterPro domain: IPR040380

Hakai is an E3 ubiquitin ligase that disrupts cell-cell contacts in epithelial cells and is upregulated in human colon and gastric adenocarcinomas. It was identified to mediate the posttranslational downregulation of E-cadherin (CDH1), a major component of adherens junctions in epithelial cells and a potent tumour suppressor [ 1 , 2 , 3 ]. It also promotes ubiquitination of several other tyrosine-phosphorylated Src substrates, including cortactin (CTTN) and DOK1 [ 4 ].

Hakai acts as a homodimer with a novel HYB (Hakai pTyr-binding) domain that forms a phosphotyrosine-binding pocket upon, and consists of a pair of monomers arranged in an anti-parallel configuration. Each monomer contains a C3HC4-type RING-HC finger and a short pTyr-B domain that incorporates a novel, atypical C2H2-type Zn-finger coordination motif. Both domains are important for dimerization [ 5 , 5 ].

ZNF645, also known as CBLL2, is a novel testis-specific E3 ubiquitin-protein ligase that plays a role in sperm production and quality control [ 5 ]. It has a structure similar to that of the c-Cbl-like protein Hakai. In contrast to Hakai, its HYB domain demonstrates different target specificities. It interacts with v-Src-phosphorylated E-cadherin, but not to cortactin [ 6 ].

1. Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat. Cell Biol. 4, 222-31
2. Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin. EMBO J. 31, 1308-19
3. Biological influence of Hakai in cancer: a 10-year review. Cancer Metastasis Rev. 31, 375-86
4. Dimeric switch of Hakai-truncated monomers during substrate recognition: insights from solution studies and NMR structure. J. Biol. Chem. 289, 25611-23
5. Human RING finger protein ZNF645 is a novel testis-specific E3 ubiquitin ligase. Asian J. Androl. 12, 658-66