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
  • 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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