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Cbl proto-oncogene, E3 ubiquitin protein ligase-like 1
Symbols CBLL1 ; HAKAI; RNF188
External IDs OMIM606872 HomoloGene11734 GeneCards: CBLL1 Gene
Species Human Mouse
Entrez 79872 104836
Ensembl ENSG00000105879 ENSMUSG00000020659
UniProt Q75N03 Q9JIY2
RefSeq (mRNA) NM_024814 NM_001253847
RefSeq (protein) NP_079090 NP_001240776
Location (UCSC) Chr 7:
107.38 – 107.4 Mb
Chr 12:
31.48 – 31.5 Mb
PubMed search [1] [2]

The E3 ubiquitin-protein ligase Hakai (HAKAI) also known as Casitas B-lineage lymphoma-transforming sequence-like protein 1 (CBLL1) is an enzyme that in humans is encoded by the CBLL1 gene.[1] This gene encodes an E3 ubiquitin ligase for the E-cadherin complex and mediates its ubiquitination, endocytosis, and degradation in the lysosomes. The encoded protein contains a RING-finger domain and is also thought to have a role in control of cell proliferation.


Hakai functions as a RING finger domain-containing E3 ubiquitin ligase for E-cadherin. Hakai mediates E-cadherin ubiquitination and its degradation by proteasomes. "Hakai" means "destruction" in Japanese. Proteosomal degradation of E-cadherin can be regulated by phosphorylation. The Hakai binding site is a part of the E-cadherin cytoplasmic domain that contains several tyrosines.[2] Tyrosine kinases such as Src and Met can phosphorylate E-cadherin and enhance Hakai binding to E-cadherin.[3] Two lysines of the E-cadherin cytoplasmic domain have been shown to be sites for ubiquitination.[4] Hakai also interacts with polypyrimidine tract-binding protein-associated splicing factor.[5]

See also[edit]

  • CBL (gene); the gene name "CBLL1" comes from "Cbl-like protein 1"


  1. ^ Fujita Y, Krause G, Scheffner M, Zechner D, Leddy HE, Behrens J, Sommer T, Birchmeier W (March 2002). "Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex". Nat. Cell Biol. 4 (3): 222–31. doi:10.1038/ncb758. PMID 11836526. 
  2. ^ Aparicio LA, Valladares M, Blanco M, Alonso G, Figueroa A (June 2012). "Biological influence of Hakai in cancer: a 10-year review". Cancer Metastasis Rev. 31 (1-2): 375–86. doi:10.1007/s10555-012-9348-x. PMC 3350634. PMID 22349934. 
  3. ^ Mukherjee M, Chow SY, Yusoff P, Seetharaman J, Ng C, Sinniah S, Koh XW, Asgar NF, Li D, Yim D, Jackson RA, Yew J, Qian J, Iyu A, Lim YP, Zhou X, Sze SK, Guy GR, Sivaraman J (March 2012). "Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin". EMBO J. 31 (5): 1308–19. doi:10.1038/emboj.2011.496. PMC 3298002. PMID 22252131. 
  4. ^ Hartsock A, Nelson WJ (2012). "Competitive Regulation of E-Cadherin JuxtaMembrane Domain Degradation by p120-Catenin Binding and Hakai-Mediated Ubiquitination". PLoS ONE 7 (5): e37476. doi:10.1371/journal.pone.0037476. PMC 3365061. PMID 22693575.  edit
  5. ^ Figueroa A, Fujita Y, Gorospe M (November 2009). "Hacking RNA: Hakai promotes tumorigenesis by enhancing the RNA-binding function of PSF". Cell Cycle 8 (22): 3648–51. doi:10.4161/cc.8.22.9909. PMC 2808762. PMID 19855157. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.