ppGalNAc-T4-catalyzed O-Glycosylation of TGF-β type Ⅱ receptor regulates breast cancer cells metastasis potential
| Autor: | Wenli Li, Tianmiao Huang, Qiushi Chen, Qiong Wu, Sijin Wu, Nana Zhang, Cheng Zhang, Jianing Zhang, Huang Huang, Xue Wang, Keren Zhang, Yubo Liu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Glycosylation PDAC pancreatic ductal adenocarcinoma Receptor Transforming Growth Factor-beta Type I GEPIA Gene Expression Profiling Interactive Analysis Biochemistry DMEM Dulbecco’s modified Eagle’s medium Metastasis Transforming Growth Factor beta GEO Gene Expression Omnibus Receptor epithelial–mesenchymal transition (EMT) CL claudin-low biology Chemistry ppGalNAc-T4 IP immunoprecipitation O-GalNAc glycosylation MD molecular dynamics RFS recurrence-free survival CRC colorectal cancer shRNA short hairpin RNA Female EMT epithelial–mesenchymal transition Research Article Cell signaling TGF-β type Ⅰ and Ⅱ receptors Epithelial-Mesenchymal Transition BL basal-like Breast Neoplasms VVL Vicia villosa lectin 03 medical and health sciences Breast cancer breast cancer FBS fetal bovine serum PDB Protein Data Bank TGF-β transforming growth factor beta medicine Humans Epithelial–mesenchymal transition Molecular Biology 030102 biochemistry & molecular biology co-IP coimmunoprecipitation Cell Biology Transforming growth factor beta Claudin-Low medicine.disease WT wild-type 030104 developmental biology Cancer research biology.protein Transforming growth factor |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | GalNAc-type O-glycosylation, initially catalyzed by polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts), is one of the most abundant and complex post-translational modifications of proteins. Emerging evidence has proven that aberrant ppGalNAc-Ts are involved in malignant tumor transformation. However, the exact molecular functions of ppGalNAc-Ts are still unclear. Here, the role of one isoform, ppGalNAc-T4, in breast cancer cell lines was investigated. The expression of ppGalNAc-T4 was found to be negatively associated with migration of breast cancer cells. Loss-of function studies revealed that ppGalNAc-T4 attenuated the migration and invasion of breast cancer cells by inhibiting the epithelial-mesenchymal transition (EMT) process. Correspondingly, transforming growth factor beta (TGF-β) signaling, which is the upstream pathway of EMT, was impaired by ppGalNAc-T4 expression. ppGalNAc-T4 knock-out decreased O-GalNAc modification of TGF-β type Ⅰ and Ⅱ receptor (TβR Ⅰ and Ⅱ) and led to the elevation of TGF-β receptor dimerization and activity. Importantly, a peptide from TβR Ⅱ was identified as a naked peptide substrate of ppGalNAc-T4 with a higher affinity than ppGalNAc-T2. Further, Ser31, corresponding to the extracellular domain of TβR Ⅱ, was identified as the O-GalNAcylation site upon in vitro glycosylation by ppGalNAc-T4. The O-GalNAc-deficient S31A mutation enhanced TGF-β signaling activity and EMT in breast cancer cells. Together, these results identified a novel mechanism of ppGalNAc-T4-catalyzed TGF-β receptors O-GalNAcylation that suppresses breast cancer cell migration and invasion via the EMT process. Targeting ppGalNAc-T4 may be a potential therapeutic strategy for breast cancer treatment. |
| Databáze: | OpenAIRE |
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