Wip1 regulates Smad4 phosphorylation and inhibits TGF‐β signaling

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. Synopsis Phosphorylation of Smad4, a central mediator of TGF‐β signaling, plays a pivotal role in controlling its activity and stability. Here, Wip1‐mediated dephosphorylation of Smad4 in its linker region is identified as a novel regulatory mechanism of TGF‐β signaling. Wip1 negatively controls gene responses induced by TGF‐β/Activin/Nodal or BMP signals. Wip1 directly dephosphorylates Smad4 at Thr277 in its linker region, regulating its nuclear retention and half‐life. Wip1 restricts mesoderm formation and favours neural differentiation by dephosphorylating Smad4 in Xenopus . Wip1 restrains migration of cancer cells, but promotes their tumourigenicity by down‐regulating Smad4 activity. Graphical Abstract Phosphorylation of Smad4, a central mediator of TGF‐β signaling, plays a pivotal role in controlling its activity and stability. Here, Wip1‐mediated dephosphorylation of Smad4 in its linker region is identified as a novel regulatory mechanism of TGF‐β signaling.