title: Migfilin regulates esophageal cancer cell motility through promoting GSK-3β-mediated degradation of β-catenin.
abstract: Migfilin, a protein component of focal adhesions, has been implicated in regulation of cell-extracellular matrix adhesion and motility but the underlying mechanisms are not fully elucidated. In this study, we have determined the functions of migfilin in esophageal cancer cells and the mechanisms involved. We show that the expression level of migfilin is negatively associated with clinical metastasis, and enforced expression of migfilin suppressed cell motility through decreased free β-catenin level. Overexpression of migfilin resulted in destabilization of β-catenin in concomitance with reduction of its transcriptional activity. Knockdown of migfilin by siRNA, transfection of a mutant β-catenin at Ser37 which is a critical phosphorylation site of GSK-3β, GSK-3β inhibitor LiCl, or proteasome inhibitor MG132 reversed the migfilin-mediated β-catenin degradation and transcription inhibition. Moreover, migfilin promoted β-catenin degradation by reinforcing the association between β-catenin and GSK-3β. In addition, exogenously expressed β-catenin partially restored migfilin-induced suppression of cell invasion. Collectively, these results suggest that the expression level of migfilin in ESCCs is inversely correlated with clinical metastasis status, and migfilin inhibits ESCC cell invasion at least in part through promoting degradation of β-catenin.
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Huan
authors.initials: H
authors.lastname: He
authors.forename: Fang
authors.initials: F
authors.lastname: Ding
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Aiping
authors.initials: A
authors.lastname: Luo
authors.forename: Hongyan
authors.initials: H
authors.lastname: Chen
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wu
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Liu
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; C473794:FBLIM1 protein, human; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex