title: The Small C-terminal Domain Phosphatase 1 Inhibits Cancer Cell Migration and Invasion by Dephosphorylating Ser(P)68-Twist1 to Accelerate Twist1 Protein Degradation.
abstract: 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.
authors.affiliation: From the Department of Molecular and Cellular Biology.
authors.forename: Tong
authors.initials: T
authors.lastname: Sun
authors.affiliation: From the Department of Molecular and Cellular Biology, the Institute for Cancer Medicine, Research Center for Preclinical Medicine and College of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, China, and.
authors.forename: Junjiang
authors.initials: J
authors.lastname: Fu
authors.affiliation: From the Department of Molecular and Cellular Biology.
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.affiliation: Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
authors.affiliation: From the Department of Molecular and Cellular Biology.
authors.forename: Lan
authors.initials: L
authors.lastname: Liao
authors.affiliation: From the Department of Molecular and Cellular Biology, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, the Life Sciences Institute and Innovation Center for Cell Signaling Networks, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.affiliation: From the Department of Molecular and Cellular Biology, the Institute for Cancer Medicine, Research Center for Preclinical Medicine and College of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, China, and jxu@bcm.edu.
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000072417:Protein Domains; D059748:Proteolysis; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D012694:Serine; D020929:Mitogen-Activated Protein Kinase Kinases; C413483:CTDSP1 protein, human; D010749:Phosphoprotein Phosphatases
keywords: breast cancer; cell signaling; epithelial-mesenchymal transition (EMT); gene regulation; molecular cell biology; protein interaction; protein phosphatase