Wip1 regulates Smad4 phosphorylation and inhibits <scp>TGF</scp>‐β signaling

Park, Dong‐Seok; Yoon, Gang-Ho; Kim, Eun Young; Lee, Taehyeong; Kim, Kyuhee; Lee, Peter Cw; Chang, Eun‐Ju; Choi, Sun‐Cheol

doi:10.15252/embr.201948693

Cited by 18 publications

(16 citation statements)

References 44 publications

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“…Depending on cancer stage, Smad4 can mediate cytostasis (early stage) or promote invasion and metastasis (late stage). In agreement with this notion, Park and colleagues found that depletion of Wip1 promoted TGF‐β‐induced growth arrest of human embryonic kidney cells and also enhanced TGF‐β‐induced migration of aggressive human breast cancer cells . Small molecule Wip1 phosphatase inhibitors are currently being explored for cancer therapy.…”

Section: Wip1 Dephosphorylates Smad4 At Thr277 In the Linker Region supporting

confidence: 79%

“…In addition, methylation at Arg272 by protein arginine methyltransferase 1 was shown to be required for GSK3‐mediated phosphorylation of Smad4 (Fig ). In line with these results, Park et al now found that Wip1 antagonized FGF‐induced Erk kinase Smad4 Thr277 phosphorylation and prevented Smad4 degradation. The latter effect was also observed following Wnt stimulation, which inhibits GSK3‐induced phosphorylation and prevents recruitment of the βTrCP1 (Fig ).…”

Section: Wip1 Dephosphorylates Smad4 At Thr277 In the Linker Region mentioning

confidence: 99%

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Controlling Smad4 signaling with a Wip

Dijke

Baker

2020

EMBO Reports

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Members of the transforming growth factor-b (TGF-b) family play key roles in embryogenesis and in maintaining tissue homeostasis, and their perturbation can result in a broad range of diseases. One way TGF-b family signaling pathways are kept in check is by reversible (de)phosphorylation of intracellular Smad effectors. In this issue of EMBO Reports, Park et al [1] identify the phosphatase wild-type p53induced phosphatase 1 (Wip1) as a negative regulator of TGF-b family signaling. Mechanistically, Wip1 constrains TGF-b family signaling through direct dephosphorylation of Thr277, an activating MAP kinase phosphorylation site located in the linker region of the common mediator Smad4.EMBO Reports (2020) 21: e50246 See also: DS Park et al (May 2020)T he TGF-b family, comprising TGF-bs, activins, nodal, and bone morphogenic proteins (BMPs), controls a broad spectrum of cellular responses via their transmembrane serine/threonine kinase type I and type II receptors. Upon ligand-induced type I/type II receptor complex formation, intracellular receptorregulated (R)-Smad effector proteins become activated following phosphorylation of two C-terminal serine residues. These activated R-Smads interact with Smad4, a signaling component that is shared by multiple TGF-b family members. Smad heteromeric complexes accumulate in the nucleus where they act as sequence-specific DNA-binding transcription factors. Smads harbor two conserved Mad Homology (MH) domains, MH1 and MH2, located at their amino and carboxy termini, respectively. These domains are connected via a flexible prolinerich linker region. The MH1 domain interacts with DNA, and the MH2 domain is involved in R-Smad-Smad4 complex formation [2].

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Section: Wip1 Dephosphorylates Smad4 At Thr277 In the Linker Region supporting

confidence: 79%

Section: Wip1 Dephosphorylates Smad4 At Thr277 In the Linker Region mentioning

confidence: 99%

Controlling Smad4 signaling with a Wip

Dijke

Baker

2020

EMBO Reports

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“…The importance of MAPK in mediating the oncogenic function of TGF-β is exemplified by the fact that the Smad4 phosphatase Wip1 can restrain the TGF-β-induced cell growth arrest, migration, and invasion and enhances the tumorigenicity of cancer cells by repressing Smad4 activity via antagonising MAPK function. Mechanistically, Wip1 selectively dephosphorylates Smad4 at a specific MAPK phosphorylation site to inhibit its nuclear accumulation and stability [ 22 ].…”

Section: Tgf-β In Cancer Initiation and Progressionmentioning

confidence: 99%

Transforming Growth Factor-β: A Multifunctional Regulator of Cancer Immunity

Xue

Chung

Córdoba

et al. 2020

Cancers

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Transforming growth factor-β (TGF-β) was originally identified as an anti-tumour cytokine. However, there is increasing evidence that it has important roles in the tumour microenvironment (TME) in facilitating cancer progression. TGF-β actively shapes the TME via modulating the host immunity. These actions are highly cell-type specific and complicated, involving both canonical and non-canonical pathways. In this review, we systemically update how TGF-β signalling acts as a checkpoint regulator for cancer immunomodulation. A better appreciation of the underlying pathogenic mechanisms at the molecular level can lead to the discovery of novel and more effective therapeutic strategies for cancer.

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“…Wip1 is an important oncogenic protein that has already been found to be highly expressed in multiple types of tumour cells in original research. 24 Wip1 has been recently reported to negatively regulate peripheral inflammation. 25 In addition, in recent years, an increasing number of studies have begun to focus on the role of Wip1 in the CNS.…”

Section: Discussionmentioning

confidence: 99%

Loss of Wip1 aggravates brain injury after ischaemia/reperfusion by overactivating microglia

et al. 2021

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Background and purposeThe inflammatory response mediated by microglia/macrophages is closely related to cerebral ischaemia/reperfusion injury. Wild-type p53-induced protein phosphatase 1 (Wip1), a serine/threonine phosphatase, is expressed in various tissues. A growing number of reports have suggested that Wip1 is a negative regulator of inflammation in peripheral tissue; however, its role in the central nervous system (CNS) remains unclear. This study aimed to clarify whether Wip1 can inhibit CNS inflammation by regulating microglia/macrophage functions after ischaemic injury.MethodsA model of middle cerebral artery occlusion and reperfusion was established in mice. CNS inflammation was simulated by lipopolysaccharide treatment of primary microglia. Laser speckle imaging was used to monitor regional cerebral blood flow. Behavioural outcomes were assessed with a TreadScan gait analysis system. TTC staining was used to evaluate the infarct volume, and western blotting and immunofluorescence staining were applied to detect the phenotypical transformation of microglia. ELISA was performed to detect the levels of inflammatory factors.ResultsWip1 expression was increased after ischaemia/reperfusion. Wip1-knockout (KO) mice displayed more severe brain injury than wild-type mice, as indicated by aggravated motor dysfunction, greater brain infarct volumes and higher expression of inflammatory cytokines (interleukin-6 and tumour necrosis factor alpha) in the brain. We also found that Wip1 depletion increased microglial/macrophage activation in both in vitro and in vivo models, which all showed activation of microglia/macrophages. Lentivirus-Ppm1d reversed the injury induced by Wip1-KO.ConclusionsOur results suggest that Wip1 may inhibit neuroinflammation by inhibiting microglial/macrophage activation after brain ischaemia/reperfusion injury.

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Wip1 regulates Smad4 phosphorylation and inhibits TGF‐β signaling

Cited by 18 publications

References 44 publications

Controlling Smad4 signaling with a Wip

Controlling Smad4 signaling with a Wip

Transforming Growth Factor-β: A Multifunctional Regulator of Cancer Immunity

Loss of Wip1 aggravates brain injury after ischaemia/reperfusion by overactivating microglia

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