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Wip1 regulates Smad4 phosphorylation and inhibits TGF-? signaling

ABSTRACT: The tumor suppressor Smad4, a key mediator of the TGF-?/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-?/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-?/BMP signals. Wip1 restrains TGF-?-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-? signaling.

SUBMITTER: Dr. Dong-Seok Park

PROVIDER: S-SCDT-EMBOR-2019-48693-T | biostudies-other |

REPOSITORIES: biostudies-other

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DACH1 inhibits TGF-beta signaling through binding Smad4

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