Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development

Seung Ju Cho, Bok Sik Cha, Ok Seon Kwon, Jisun Lim, Dong Myung Shin, Dong Wook Han, Tohru Ishitani, Eek hoon Jho, Albert J. Fornace, Hyuk Jin Cha

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1013-1022
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1863
Issue number4
DOIs
Publication statusPublished - Apr 1 2017

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Phosphoric Monoester Hydrolases
Germ Cells
Phosphotransferases
Lymphoid Enhancer-Binding Factor 1
Testis
Catenins
p38 Mitogen-Activated Protein Kinases
Spermatogenesis
Transgenic Mice
Fertility
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

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Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development. / Cho, Seung Ju; Cha, Bok Sik; Kwon, Ok Seon; Lim, Jisun; Shin, Dong Myung; Han, Dong Wook; Ishitani, Tohru; Jho, Eek hoon; Fornace, Albert J.; Cha, Hyuk Jin.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1863, No. 4, 01.04.2017, p. 1013-1022.

Research output: Contribution to journalArticle

Cho, SJ, Cha, BS, Kwon, OS, Lim, J, Shin, DM, Han, DW, Ishitani, T, Jho, EH, Fornace, AJ & Cha, HJ 2017, 'Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development', Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1863, no. 4, pp. 1013-1022. https://doi.org/10.1016/j.bbadis.2017.01.028
Cho, Seung Ju ; Cha, Bok Sik ; Kwon, Ok Seon ; Lim, Jisun ; Shin, Dong Myung ; Han, Dong Wook ; Ishitani, Tohru ; Jho, Eek hoon ; Fornace, Albert J. ; Cha, Hyuk Jin. / Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2017 ; Vol. 1863, No. 4. pp. 1013-1022.
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