Volume 8 Issue 3, Mar 2023:
Article
B-lymphoid tyrosine kinase-mediated FAM83A phosphorylation elevates pancreatic tumorigenesis through interacting with β-catenin
Cefan Zhou
ORCID: orcid.org/0000-0003-0680-3843,Xiaoting Zhu,Nanxi Liu,Xueying Dong,Xuewen Zhang,Huili Huang,Yu Tang,Shicheng Liu,Mengyu Hu,Ming Wang
ORCID: orcid.org/0000-0002-2836-1217,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
ORCID: orcid.org/0000-0002-5524-4518
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.
