title: Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development.
abstract: Mice null for wild-type p53-induced phosphatase 1 (WIP1) display defects in testis development and spermatogenesis, resulting in reduced fertility. However, the molecular mechanism underlying these abnormalities in the testis remains uncharacterized. We report that the phosphatase activity of WIP1 increases Wnt activity through Nemo-like kinase (NLK). WIP1 directly interacted with NLK, which is highly homologous to p38 MAPK, a WIP1 substrate, and dephosphorylated its activation site. The WIP1-mediated inhibition of NLK activity markedly decreased the phosphorylation of lymphoid enhancer-binding factor 1 (LEF1), enhancing its interaction with β-catenin. Additionally, WIP1 depletion impaired germ cell development, as evidenced by the expression of Oct4 and the germ cell-specific markers Ddx4, Nanos3 and Dnd1 during the development of germ cells from Oct4-GFP transgenic (OG2) mouse embryonic stem cells (mESCs). The expression of WIP1, whose level was significantly lower after the differentiation of germ cells from mESCs, occurred in parallel with the expression of germ cell development markers and SRY-box 17 (Sox17), a downstream target of Wnt. These results indicate that WIP1 is essential for germ cell development, which is known to require Wnt activity.
authors.affiliation: College of Natural Sciences, Dept. of Life Sciences, Sogang University, Seoul, Republic of Korea.
authors.forename: Seung-Ju
authors.initials: SJ
authors.lastname: Cho
authors.affiliation: Department of Life Science, University of Seoul, Seoul, Republic of Korea.
authors.forename: Bok-Sik
authors.initials: BS
authors.lastname: Cha
authors.affiliation: College of Natural Sciences, Dept. of Life Sciences, Sogang University, Seoul, Republic of Korea.
authors.forename: Ok-Seon
authors.initials: OS
authors.lastname: Kwon
authors.affiliation: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jisun
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Dong-Myung
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Department of Bioscience and Biotechnology, Bio-Organ Research Center, Konkuk University, Seoul, Republic of Korea.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Han
authors.affiliation: Division of Cell Regulation Systems, Medical Institute of Bioregulation Kyushu University, Fukuoka, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Ishitani
authors.affiliation: Department of Life Science, University of Seoul, Seoul, Republic of Korea.
authors.forename: Eek-Hoon
authors.initials: EH
authors.lastname: Jho
authors.affiliation: Georgetown University, Dept. of Biochemistry and Molecular & Cellular Biology, Dept. of Oncology, Washington, DC 20057, USA. Electronic address: af294@georgetown.edu.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.affiliation: College of Natural Sciences, Dept. of Life Sciences, Sogang University, Seoul, Republic of Korea. Electronic address: hjcha@sogang.ac.kr.
authors.forename: Hyuk-Jin
authors.initials: HJ
authors.lastname: Cha
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000166:cytology* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D013737:Testis / Q000166:cytology / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D051153:Wnt Proteins; D051176:beta Catenin; C408347:Nlk protein, mouse; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C
keywords: Dephosphorylation; Germ cell development; NLK; Wip1; β-catenin