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.

中文翻译：

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Wip1 调节 Smad4 磷酸化并抑制 TGF-β 信号传导。

肿瘤抑制因子 Smad4 是 TGF-β/BMP 通路的关键介质，对于发育和组织稳态至关重要。Smad4 在其连接区中由丝裂原激活蛋白激酶 (MAPK) 催化的磷酸化在调节其转录活性和稳定性方面发挥着关键作用。相比之下，Smad4 去磷酸化作为 TGF-β/BMP 信号传导的控制机制以及负责其去磷酸化的磷酸酶的作用迄今为止仍然难以捉摸。在这里，我们将 Wip1 鉴定为 Smad4 磷酸酶。Wip1 选择性结合 Smad4 的 Thr277（关键的 MAPK 磷酸化位点）并使其去磷酸化，从而调节其核积累和半衰期。在非洲爪蟾胚胎中，Wip1 通过抑制 TGF-β/BMP 信号限制中胚层形成并有利于神经诱导。Wip1 抑制 TGF-β 诱导的人类细胞生长停滞、迁移和侵袭，并通过抑制 Smad4 的抗有丝分裂活性增强癌细胞的致瘤性。我们认为 Smad4 的 Wip1 依赖性去磷酸化对于 TGF-β 信号传导的调节至关重要。