title: Tumor Suppressor Lzap Suppresses Wnt/β-Catenin Signaling to Promote Zebrafish Embryonic Ventral Cell Fates via the Suppression of Inhibitory Phosphorylation of Glycogen Synthase Kinase 3.
abstract: Wnt/β-catenin signaling controls various cell fates in metazoan development, and its dysregulation is often associated with cancer formation. However, regulations of this signaling pathway are not completely understood. Here, we report that Lzap, a tumor suppressor, controls nuclear translocation of β-catenin. In zebrafish embryos disruption of lzap increases the expression of chordin (chd), which encodes a bone morphogenetic protein (BMP) antagonist that is localized in prospective dorsal cells and promotes dorsal fates. Consistently, lzap-deficient embryos with attenuated BMP signaling are dorsalized, which can be rescued by overexpression of zebrafish lzap or bmp2b or human LZAP. The expansion of chd expression in embryos lacking lzap is due to the accumulation of nuclear β-catenin in ventral cells, in which β-catenin is usually degraded. Furthermore, the activity of GSK3, a master regulator of β-catenin degradation, is suppressed in lzap-deficient embryos via inhibitory phosphorylation. Finally, we also report that a similar regulatory axis is also likely to be present in a human tongue carcinoma cell line, SAS. Our results reveal that Lzap is a novel regulator of GSK3 for the maintenance of ventral cell properties and may prevent carcinogenesis via the regulation of β-catenin degradation.
authors.affiliation: From the Institute of Cellular and Organismic Biology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 11529, Taiwan, Department of BioAgricultural Science, National Chiayi University, Chiayi 60004, Taiwan, and.
authors.forename: Kun-Yang
authors.initials: KY
authors.lastname: Lin
authors.affiliation: From the Institute of Cellular and Organismic Biology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 11529, Taiwan.
authors.forename: Shih-Han
authors.initials: SH
authors.lastname: Kao
authors.affiliation: From the Institute of Cellular and Organismic Biology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 11529, Taiwan, Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, National Chung-Hsing University and Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Lai
authors.affiliation: Department of BioAgricultural Science, National Chiayi University, Chiayi 60004, Taiwan, and.
authors.forename: Ciao-Ting
authors.initials: CT
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung City 80424, Taiwan.
authors.forename: Chang-Yi
authors.initials: CY
authors.lastname: Wu
authors.affiliation: From the Institute of Cellular and Organismic Biology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 11529, Taiwan, cohsu@gate.sinica.edu.tw.
authors.forename: Hwei-Jan
authors.initials: HJ
authors.lastname: Hsu
authors.affiliation: Department of BioAgricultural Science, National Chiayi University, Chiayi 60004, Taiwan, and wangw4@mail.ncyu.edu.tw.
authors.forename: Wen-Der
authors.initials: WD
authors.lastname: Wang
mesh_terms: D000818:Animals; D019070:Cell Lineage; D016147:Genes, Tumor Suppressor; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C561480:CDK5Rap3 protein, zebrafish; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3
keywords: Cdk5rap3; Chordin; Wnt signaling; bone morphogenetic protein (BMP); dorsal-ventral patterning; glycogen synthase kinase 3 (GSK-3); tumor suppressor gene; β-catenin (B-catenin)