B-lymphoid tyrosine kinase-mediated FAM83A phosphorylation elevates pancreatic tumorigenesis through interacting with β-catenin
Abstract Abnormal activation of Wnt/β-catenin-mediated transcription is closely associated with the malignancy of pancreatic cancer. Family with sequence similarity 83 member A (FAM83A) was shown recently to have oncogenic effects in a variety of cancer types, but the biological roles and molecular...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-02-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-022-01268-5 |
| _version_ | 1797863399721271296 |
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| author | Cefan Zhou Xiaoting Zhu Nanxi Liu Xueying Dong Xuewen Zhang Huili Huang Yu Tang Shicheng Liu Mengyu Hu Ming Wang Xiaoling Deng Shi Li Rui Zhang Yuan Huang Hao Lyu Shuai Xiao Sang Luo Declan William Ali Marek Michalak Xing-Zhen Chen Zhentian Wang Jingfeng Tang |
| author_facet | Cefan Zhou Xiaoting Zhu Nanxi Liu Xueying Dong Xuewen Zhang Huili Huang Yu Tang Shicheng Liu Mengyu Hu Ming Wang Xiaoling Deng Shi Li Rui Zhang Yuan Huang Hao Lyu Shuai Xiao Sang Luo Declan William Ali Marek Michalak Xing-Zhen Chen Zhentian Wang Jingfeng Tang |
| author_sort | Cefan Zhou |
| collection | DOAJ |
| description | Abstract Abnormal activation of Wnt/β-catenin-mediated transcription is closely associated with the malignancy of pancreatic cancer. Family with sequence similarity 83 member A (FAM83A) was shown recently to have oncogenic effects in a variety of cancer types, but the biological roles and molecular mechanisms of FAM83A in pancreatic cancer need further investigation. Here, we newly discovered that FAM83A binds directly to β-catenin and inhibits the assembly of the cytoplasmic destruction complex thus inhibiting the subsequent phosphorylation and degradation. FAM83A is mainly phosphorylated by the SRC non-receptor kinase family member BLK (B-lymphoid tyrosine kinase) at tyrosine 138 residue within the DUF1669 domain that mediates the FAM83A-β-catenin interaction. Moreover, FAM83A tyrosine 138 phosphorylation enhances oncogenic Wnt/β-catenin-mediated transcription through promoting β-catenin-TCF4 interaction and showed an elevated nucleus translocation, which inhibits the recruitment of histone deacetylases by TCF4. We also showed that FAM83A is a direct downstream target of Wnt/β-catenin signaling and correlates with the levels of Wnt target genes in human clinical pancreatic cancer tissues. Notably, the inhibitory peptides that target the FAM83A-β-catenin interaction significantly suppressed pancreatic cancer growth and metastasis in vitro and in vivo. Our results revealed that blocking the FAM83A cascade signaling defines a therapeutic target in human pancreatic cancer. |
| first_indexed | 2024-04-09T22:36:00Z |
| format | Article |
| id | doaj.art-6677a799049d4774a5a820c4780176b0 |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-04-09T22:36:00Z |
| publishDate | 2023-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-6677a799049d4774a5a820c4780176b02023-03-22T12:30:42ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352023-02-018111810.1038/s41392-022-01268-5B-lymphoid tyrosine kinase-mediated FAM83A phosphorylation elevates pancreatic tumorigenesis through interacting with β-cateninCefan Zhou0Xiaoting Zhu1Nanxi Liu2Xueying Dong3Xuewen Zhang4Huili Huang5Yu Tang6Shicheng Liu7Mengyu Hu8Ming Wang9Xiaoling Deng10Shi Li11Rui Zhang12Yuan Huang13Hao Lyu14Shuai Xiao15Sang Luo16Declan William Ali17Marek Michalak18Xing-Zhen Chen19Zhentian Wang20Jingfeng Tang21National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyDepartment of Clinical Laboratory, Renmin Hospital of Wuhan UniversityNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyNingxia Key Laboratory of Stem Cell and Regenerative Medicine, General Hospital of Ningxia Medical UniversityDepartment of Biological Sciences, University of AlbertaDepartment of Biochemistry, University of AlbertaMembrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of AlbertaDepartment of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, and Shanghai Fifth People’s Hospital, Fudan UniversityNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of TechnologyAbstract Abnormal activation of Wnt/β-catenin-mediated transcription is closely associated with the malignancy of pancreatic cancer. Family with sequence similarity 83 member A (FAM83A) was shown recently to have oncogenic effects in a variety of cancer types, but the biological roles and molecular mechanisms of FAM83A in pancreatic cancer need further investigation. Here, we newly discovered that FAM83A binds directly to β-catenin and inhibits the assembly of the cytoplasmic destruction complex thus inhibiting the subsequent phosphorylation and degradation. FAM83A is mainly phosphorylated by the SRC non-receptor kinase family member BLK (B-lymphoid tyrosine kinase) at tyrosine 138 residue within the DUF1669 domain that mediates the FAM83A-β-catenin interaction. Moreover, FAM83A tyrosine 138 phosphorylation enhances oncogenic Wnt/β-catenin-mediated transcription through promoting β-catenin-TCF4 interaction and showed an elevated nucleus translocation, which inhibits the recruitment of histone deacetylases by TCF4. We also showed that FAM83A is a direct downstream target of Wnt/β-catenin signaling and correlates with the levels of Wnt target genes in human clinical pancreatic cancer tissues. Notably, the inhibitory peptides that target the FAM83A-β-catenin interaction significantly suppressed pancreatic cancer growth and metastasis in vitro and in vivo. Our results revealed that blocking the FAM83A cascade signaling defines a therapeutic target in human pancreatic cancer.https://doi.org/10.1038/s41392-022-01268-5 |
| spellingShingle | Cefan Zhou Xiaoting Zhu Nanxi Liu Xueying Dong Xuewen Zhang Huili Huang Yu Tang Shicheng Liu Mengyu Hu Ming Wang Xiaoling Deng Shi Li Rui Zhang Yuan Huang Hao Lyu Shuai Xiao Sang Luo Declan William Ali Marek Michalak Xing-Zhen Chen Zhentian Wang Jingfeng Tang B-lymphoid tyrosine kinase-mediated FAM83A phosphorylation elevates pancreatic tumorigenesis through interacting with β-catenin Signal Transduction and Targeted Therapy |
| title | B-lymphoid tyrosine kinase-mediated FAM83A phosphorylation elevates pancreatic tumorigenesis through interacting with β-catenin |
| title_full | B-lymphoid tyrosine kinase-mediated FAM83A phosphorylation elevates pancreatic tumorigenesis through interacting with β-catenin |
| title_fullStr | B-lymphoid tyrosine kinase-mediated FAM83A phosphorylation elevates pancreatic tumorigenesis through interacting with β-catenin |
| title_full_unstemmed | B-lymphoid tyrosine kinase-mediated FAM83A phosphorylation elevates pancreatic tumorigenesis through interacting with β-catenin |
| title_short | B-lymphoid tyrosine kinase-mediated FAM83A phosphorylation elevates pancreatic tumorigenesis through interacting with β-catenin |
| title_sort | b lymphoid tyrosine kinase mediated fam83a phosphorylation elevates pancreatic tumorigenesis through interacting with β catenin |
| url | https://doi.org/10.1038/s41392-022-01268-5 |
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