The Small C-terminal Domain Phosphatase 1 Inhibits Cancer Cell Migration and Invasion by Dephosphorylating Ser(P)68-Twist1 to Accelerate Twist1 Protein Degradation
| Autor: | Jianming Xu, Xia Lin, Lan Liao, Junjiang Fu, Tong Sun, Tao Shen, Xin-Hua Feng |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell signaling Epithelial-Mesenchymal Transition animal structures Phosphatase Breast Neoplasms Protein degradation Biology Biochemistry Serine 03 medical and health sciences Twist transcription factor 0302 clinical medicine Protein Domains Cell Movement Cell Line Tumor Phosphoprotein Phosphatases Humans Gene Regulation Neoplasm Invasiveness Molecular Biology Mitogen-Activated Protein Kinase Kinases Twist-Related Protein 1 fungi HEK 293 cells Nuclear Proteins Cell Biology Molecular biology 030104 developmental biology 030220 oncology & carcinogenesis Proteolysis Cancer cell Phosphorylation |
| Zdroj: | Journal of Biological Chemistry. 291:11518-11528 |
| ISSN: | 0021-9258 |
| Popis: | Twist1 is a basic helix-loop-helix transcription factor that strongly promotes epithelial-to-mesenchymal transition, migration, invasion, and metastasis of cancer cells. The MAPK-phosphorylated Twist1 on its serine 68 (Ser(P)(68)-Twist1) has a significantly enhanced stability and function to drive cancer cell invasion and metastasis. However, the phosphatase that dephosphorylates Ser(P)(68)-Twist1 and destabilizes Twist1 has not been identified and characterized. In this study, we screened a serine/threonine phosphatase cDNA expression library in HEK293T cells with ectopically coexpressed Twist1. We found that the small C-terminal domain phosphatase 1 (SCP1) specifically dephosphorylates Ser(P)(68)-Twist1 in both cell-free reactions and living cells. SCP1 uses its amino acid residues 43-63 to interact with the N terminus of Twist1. Increased SCP1 expression in cells decreased Ser(P)(68)-Twist1 and total Twist1 proteins, whereas knockdown of SCP1 increased Ser(P)(68)-Twist1 and total Twist1 proteins. Furthermore, the levels of SCP1 are negatively correlated with Twist1 protein levels in several cancer cell lines. SCP1-dephosphorylated Twist1 undergoes fast degradation via the ubiquitin-proteasome pathway. Importantly, an increase in SCP1 expression in breast cancer cells with either endogenous or ectopically expressed Twist1 largely inhibits the Twist1-induced epithelial-to-mesenchymal transition phenotype and the migration and invasion capabilities of these cells. These results indicate that SCP1 is the phosphatase that counterregulates the MAPK-mediated phosphorylation of Ser(68)-Twist1. Thus, an increase in SCP1 expression and activity may be a useful strategy for eliminating the detrimental roles of Twist1 in cancer cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|