|Cbl proto-oncogene, E3 ubiquitin protein ligase-like 1|
|Symbols||; HAKAI; RNF188|
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. 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. Tyrosine kinases such as Src and Met can phosphorylate E-cadherin and enhance Hakai binding to E-cadherin. Two lysines of the E-cadherin cytoplasmic domain have been shown to be sites for ubiquitination. Hakai also interacts with polypyrimidine tract-binding protein-associated splicing factor.
- CBL (gene); the gene name "CBLL1" comes from "Cbl-like protein 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.
- 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.
- 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.
- 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.
- 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.