2. Academic Validation
  3. B-lymphoid tyrosine kinase-mediated FAM83A phosphorylation elevates pancreatic tumorigenesis through interacting with β-catenin

B-lymphoid tyrosine kinase-mediated FAM83A phosphorylation elevates pancreatic tumorigenesis through interacting with β-catenin

  • Signal Transduct Target Ther. 2023 Feb 17;8(1):66. doi: 10.1038/s41392-022-01268-5.
Cefan Zhou # 1 2,  Xiaoting Zhu # 1,  Nanxi Liu # 1 3,  Xueying Dong 1,  Xuewen Zhang 1,  Huili Huang 1 4,  Yu Tang 1,  Shicheng Liu 1,  Mengyu Hu 1,  Ming Wang 5,  Xiaoling Deng 1,  Shi Li 1,  Rui Zhang 1,  Yuan Huang 1,  Hao Lyu 1,  Shuai Xiao 1,  Sang Luo 6,  Declan William Ali 7,  Marek Michalak 8,  Xing-Zhen Chen 2,  Zhentian Wang 9,  Jingfeng Tang 10
Affiliations

Affiliations

  • 1 National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, 430068, China.
  • 2 Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G2R3, Canada.
  • 3 Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China.
  • 4 Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, and Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200433, China.
  • 5 Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 6 Ningxia Key Laboratory of Stem Cell and Regenerative Medicine, General Hospital of Ningxia Medical University, Ningxia, 750001, China.
  • 7 Department of Biological Sciences, University of Alberta, Edmonton, AB, T6G2R3, Canada.
  • 8 Department of Biochemistry, University of Alberta, Edmonton, AB, T6G2R3, Canada.
  • 9 Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, and Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200433, China. [email protected].
  • 10 National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, 430068, China. [email protected].
  • # Contributed equally.
PMID: 36797256 DOI: 10.1038/s41392-022-01268-5
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.

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