Beyond destruction: emerging roles of the E3 ubiquitin ligase Hakai
Abstract Hakai protein (CBLL1 gene) was identified as an E3 ubiquitin ligase of E-cadherin complex, inducing its ubiquitination and degradation, thus inducing epithelial-to-mesenchymal transition. Most of the knowledge about the protein was associated to its E3 ubiquitin ligase canonical role. Howev...
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| Language: | English |
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BMC
2025-01-01
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| Series: | Cellular & Molecular Biology Letters |
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| Online Access: | https://doi.org/10.1186/s11658-025-00693-y |
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| author | Juan-José Escuder-Rodríguez Andrea Rodríguez-Alonso Lía Jove Macarena Quiroga Gloria Alfonsín Angélica Figueroa |
| author_facet | Juan-José Escuder-Rodríguez Andrea Rodríguez-Alonso Lía Jove Macarena Quiroga Gloria Alfonsín Angélica Figueroa |
| author_sort | Juan-José Escuder-Rodríguez |
| collection | DOAJ |
| description | Abstract Hakai protein (CBLL1 gene) was identified as an E3 ubiquitin ligase of E-cadherin complex, inducing its ubiquitination and degradation, thus inducing epithelial-to-mesenchymal transition. Most of the knowledge about the protein was associated to its E3 ubiquitin ligase canonical role. However, important recent published research has highlighted the noncanonical role of Hakai, independent of its E3 ubiquitin ligase activity, underscoring its involvement in the N 6-methyladenosine (m6A) writer complex and its impact on the methylation of RNA. The involvement of Hakai in this mRNA modification process has renewed the relevance of this protein as an important contributor in cancer. Moreover, Hakai potential as a cancer biomarker and its prognostic value in malignant disease also emphasize its untapped potential in precision medicine, which would also be discussed in detail in our review. The development of the first small-molecule inhibitor that targets its atypical substrate binding domain is a promising step that could eventually lead to patient benefit, and we would cover its discovery and ongoing efforts toward its use in clinic. Graphical Abstract |
| format | Article |
| id | doaj-art-aef25725d08446aca50f2a6ba704c27c |
| institution | Kabale University |
| issn | 1689-1392 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cellular & Molecular Biology Letters |
| spelling | doaj-art-aef25725d08446aca50f2a6ba704c27c2025-01-26T12:42:57ZengBMCCellular & Molecular Biology Letters1689-13922025-01-0130112310.1186/s11658-025-00693-yBeyond destruction: emerging roles of the E3 ubiquitin ligase HakaiJuan-José Escuder-Rodríguez0Andrea Rodríguez-Alonso1Lía Jove2Macarena Quiroga3Gloria Alfonsín4Angélica Figueroa5Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC)Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC)Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC)Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC)Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC)Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC)Abstract Hakai protein (CBLL1 gene) was identified as an E3 ubiquitin ligase of E-cadherin complex, inducing its ubiquitination and degradation, thus inducing epithelial-to-mesenchymal transition. Most of the knowledge about the protein was associated to its E3 ubiquitin ligase canonical role. However, important recent published research has highlighted the noncanonical role of Hakai, independent of its E3 ubiquitin ligase activity, underscoring its involvement in the N 6-methyladenosine (m6A) writer complex and its impact on the methylation of RNA. The involvement of Hakai in this mRNA modification process has renewed the relevance of this protein as an important contributor in cancer. Moreover, Hakai potential as a cancer biomarker and its prognostic value in malignant disease also emphasize its untapped potential in precision medicine, which would also be discussed in detail in our review. The development of the first small-molecule inhibitor that targets its atypical substrate binding domain is a promising step that could eventually lead to patient benefit, and we would cover its discovery and ongoing efforts toward its use in clinic. Graphical Abstracthttps://doi.org/10.1186/s11658-025-00693-yHakaiCBLL1E3 ubiquitin ligasem6A methyltransferase complexCancerTargeted therapy |
| spellingShingle | Juan-José Escuder-Rodríguez Andrea Rodríguez-Alonso Lía Jove Macarena Quiroga Gloria Alfonsín Angélica Figueroa Beyond destruction: emerging roles of the E3 ubiquitin ligase Hakai Cellular & Molecular Biology Letters Hakai CBLL1 E3 ubiquitin ligase m6A methyltransferase complex Cancer Targeted therapy |
| title | Beyond destruction: emerging roles of the E3 ubiquitin ligase Hakai |
| title_full | Beyond destruction: emerging roles of the E3 ubiquitin ligase Hakai |
| title_fullStr | Beyond destruction: emerging roles of the E3 ubiquitin ligase Hakai |
| title_full_unstemmed | Beyond destruction: emerging roles of the E3 ubiquitin ligase Hakai |
| title_short | Beyond destruction: emerging roles of the E3 ubiquitin ligase Hakai |
| title_sort | beyond destruction emerging roles of the e3 ubiquitin ligase hakai |
| topic | Hakai CBLL1 E3 ubiquitin ligase m6A methyltransferase complex Cancer Targeted therapy |
| url | https://doi.org/10.1186/s11658-025-00693-y |
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