{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Park DS"],"funding":["NCI NIH HHS","National Research Foundation of Korea"],"pagination":["e48693"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7202204"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["21(5)"],"pubmed_abstract":["The tumor suppressor Smad4, a key mediator of the TGF-β/BMP pathways, is essential for development and tissue homeostasis. Phosphorylation of Smad4 in its linker region catalyzed by the mitogen-activated protein kinase (MAPK) plays a pivotal role in regulating its transcriptional activity and stability. In contrast, roles of Smad4 dephosphorylation as a control mechanism of TGF-β/BMP signaling and the phosphatases responsible for its dephosphorylation remain so far elusive. Here, we identify Wip1 as a Smad4 phosphatase. Wip1 selectively binds and dephosphorylates Smad4 at Thr277, a key MAPK phosphorylation site, thereby regulating its nuclear accumulation and half-life. In Xenopus embryos, Wip1 limits mesoderm formation and favors neural induction by inhibiting TGF-β/BMP signals. Wip1 restrains TGF-β-induced growth arrest, migration, and invasion in human cells and enhances the tumorigenicity of cancer cells by repressing the antimitogenic activity of Smad4. We propose that Wip1-dependent dephosphorylation of Smad4 is critical for the regulation of TGF-β signaling."],"journal":["EMBO reports"],"pubmed_title":["Wip1 regulates Smad4 phosphorylation and inhibits TGF-β signaling."],"pmcid":["PMC7202204"],"funding_grant_id":["2019R1H1A2080117","T32 CA009594","2016R1A2B4013355"],"pubmed_authors":["Kim EY","Choi SC","Park DS","Kim K","Lee PC","Chang EJ","Lee T","Yoon GH"],"additional_accession":[]},"is_claimable":false,"name":"Wip1 regulates Smad4 phosphorylation and inhibits TGF-β signaling.","description":"The tumor suppressor Smad4, a key mediator of the TGF-β/BMP pathways, is essential for development and tissue homeostasis. Phosphorylation of Smad4 in its linker region catalyzed by the mitogen-activated protein kinase (MAPK) plays a pivotal role in regulating its transcriptional activity and stability. In contrast, roles of Smad4 dephosphorylation as a control mechanism of TGF-β/BMP signaling and the phosphatases responsible for its dephosphorylation remain so far elusive. Here, we identify Wip1 as a Smad4 phosphatase. Wip1 selectively binds and dephosphorylates Smad4 at Thr277, a key MAPK phosphorylation site, thereby regulating its nuclear accumulation and half-life. In Xenopus embryos, Wip1 limits mesoderm formation and favors neural induction by inhibiting TGF-β/BMP signals. Wip1 restrains TGF-β-induced growth arrest, migration, and invasion in human cells and enhances the tumorigenicity of cancer cells by repressing the antimitogenic activity of Smad4. We propose that Wip1-dependent dephosphorylation of Smad4 is critical for the regulation of TGF-β signaling.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 May","modification":"2026-06-04T06:45:33.967Z","creation":"2025-02-19T03:40:43.97Z"},"accession":"S-EPMC7202204","cross_references":{"pubmed":["32103600"],"doi":["10.15252/embr.201948693"]}}