Protein phosphatase magnesium-dependent 1A–mediated inhibition of BMP signaling is independent of Smad dephosphorylation

Kokabu, Shoichiro; Nojima, Junya; Kanomata, Kazuhiro; Ohte, Satoshi; Yoda, Tetsuya; Fukuda, Tsuyoshi; Katagiri, Takenobu

doi:10.1359/jbmr.090736

Cited by 38 publications

(26 citation statements)

References 35 publications

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“…W-20-17 cells, C3H10T1/2 cells, C2C12cells, and MC3T3-E1 cells were cultured and maintained as described previously [7,[34][35][36]. 3T3-L1 cells from ATCC (American Type Culture Collection) were grown in Dulbecco's modified Eagle's (DMEM) medium containing 10% fetal bovine serum (FBS).…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling

Kokabu¹,

Sato²,

Ohte³

et al. 2014

FEBS Letters

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Edited by Zhijie ChangKeywords: Osteoblastogenesis Osteoporosis Wnt Groucho Transducing-like enhancer of split Co-repressor a b s t r a c t Transducing-like enhancer of split 3 (TLE3), one of the Groucho/TLE family members, targets Runx2 transcription and suppresses osteoblast differentiation in bone marrow stromal cells (BMSCs). Here, we identify Wnt responsive elements of the TLE3 promoter region through comparative genomic and functional analyses and show that expression of TLE3 is increased by Wnt signaling, which is important for osteoblast differentiation. We also demonstrated that TLE3 is able to suppress canonical Wnt signaling in BMSCs. Taken together, our data suggest that induction of TLE3 by Wnt signaling is part of a negative feedback loop active during osteoblast differentiation.

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Section: Cell Culture and Transfectionmentioning

confidence: 99%

Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling

Kokabu¹,

Sato²,

Ohte³

et al. 2014

FEBS Letters

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“…Cytoplasmic phosphorylation of the linker region primes Smads for further phosphorylation, ubiquitination, and degradation, whereas nuclear Smad1 linker phosphorylation is required for efficient transcription (10-13). In addition to phosphorylation, Smad activities are negatively regulated through dephosphorylation by phosphatases, such as protein phosphatase 1A and small C-terminal phosphatases (14)(15)(16)(17).…”

mentioning

confidence: 99%

Transforming Growth Factor-β₁ Represses Bone Morphogenetic Protein–Mediated Smad Signaling in Pulmonary Artery Smooth Muscle Cells via Smad3

Upton

Davies

Tajsic

et al. 2013

Am J Respir Cell Mol Biol

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Previous studies of pulmonary arterial hypertension (PAH) have implicated excessive transforming growth factor (TGF)-b 1 signaling and reduced bone morphogenetic protein (BMP) signaling in the disease pathogenesis. Reduced BMP signaling in pulmonary artery smooth muscle cells (PASMCs) from patients with heritable PAH is a consequence of germline mutations in the BMP type II receptor (BMPR-II). We sought to establish whether the TGF-b 1 and BMP4 pathways interact in PASMCs, and if this is altered in cells with BMPR-II mutations. Control PASMCs or from patients with PAH harboring BMPR-II mutations were treated with BMP4, TGF-b 1 , or cotreated with both ligands. Signaling was assessed by examination of Smad phosphorylation, luciferase reporters, and the transcription of BMP4 or TGF-b 1 -responsive genes. TGF-b 1 attenuated BMP4-mediated inhibitors of differentiation 1/2 induction and abolished the response in BMPR-II mutant PASMCs, whereas BMP4 did not alter TGF-b 1 -mediated transcription. Activin-like kinase 5 inhibition blocked this effect, whereas cycloheximide or pharmacological inhibitors of TGF-b-activated kinase 1, extracellular signal-regulated kinase 1/2, or p38 mitogen-activated protein kinase were ineffective. BMP4 and TGF-b 1 cotreatment did not alter the activation or nuclear translocation of their respective Smad signaling proteins. Small interfering RNA for Smad3, but not Smad2, Smad6, or Smad7, reversed the inhibition by TGF-b 1 . In addition, TGF-b-activated kinase 1 inhibition blocked Smad3 phosphorylation, implying that C-terminal Smad3 phosphorylation is not required for the inhibition of BMP4 signaling by TGF-b 1 . TGF-b 1 reduces BMP4 signaling in PASMCs, a response that is exacerbated on the background of reduced BMP responsiveness due to BMPR-II mutations. These data provide a rationale for therapeutic inhibition of TGF-b 1 signaling in PAH.Keywords: pulmonary arterial hypertension; transforming growth factor beta; bone morphogenetic protein; inhibitor of differentiation Transforming growth factor (TGF)-b 1 is a pleiotropic cytokine involved in embryonic development, inflammation, angiogenesis, immune cell function, and wound healing via the regulation of cell processes, such as growth, differentiation, adhesion, migration, and apoptosis (1). Excessive TGF-b 1 production is associated with fibrotic diseases of several organs, including the lung (2) and kidney (3). Dysregulated TGF-b 1 signaling is also emerging as a key pathological process in pulmonary arterial hypertension (PAH). We recently reported enhanced pulmonary vascular TGF-b 1 signaling in the monocrotaline (MCT) rat model of PAH (MCT-PAH) (4), and inhibitors of the TGF-b 1 type I receptor, activin-like kinase 5 (ALK5), attenuated disease progression in MCT-PAH, implicating TGF-b as a pathogenic cytokine in PAH (4-6). In man, most heritable PAH (HPAH) cases are associated with germline mutations in the gene encoding bone morphogenetic protein (BMP) receptor (BMPR)-II, a member of the TGF receptor superfamily (7). Furthermore, BM...

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“…These results suggest that protein phosphatases responsible for Smad1 SXS dephosphorylation may be involved in Dox-induced Smad1 activation and upregulation. PPM1A, an interacting partner of Smad1, is one of the wellstudied phosphatases responsible for SXS dephosphorylation [34][35][36][37][38] . Strikingly, Dox treatment disrupted the interaction between endogenous PPM1A and Smad1, especially for nuclear Smad1 (Fig.…”

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confidence: 99%

A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response

et al. 2012

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DnA damage and the elicited cellular response underlie the etiology of tumorigenesis and ageing. Yet, how this response integrates inputs from cells' environmental cues remains underexplored. Here we report that the BmP-smad1 pathway, which is essential for embryonic development and tissue homeostasis, has an important role in the DnA damage response and oncogenesis. on genotoxic stress, Atm phosphorylates BmPs-activated smad1 in the nucleus on s239, which disrupts smad1 interaction with protein phosphatase PPm1A, leading to enhanced activation and upregulation of smad1. smad1 then interacts with p53 and inhibits mdm2-mediated p53 ubiquitination and degradation to regulate cell proliferation and survival. Enhanced smad1 s239 phosphorylation, and Smad1 mutations causing s239 substitution were detected in oesophageal and gastric cancer samples, respectively. These findings suggest that BmP-smad1 signalling participates in the DnA damage response via the Atm-p53 pathway, thus providing a molecular mechanism whereby BmP-smad1 loss-of-function leads to tumorigenesis, for example, juvenile polyposis and Cowden syndromes.

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Protein phosphatase magnesium-dependent 1A–mediated inhibition of BMP signaling is independent of Smad dephosphorylation

Cited by 38 publications

References 35 publications

Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling

Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling

Transforming Growth Factor-β₁ Represses Bone Morphogenetic Protein–Mediated Smad Signaling in Pulmonary Artery Smooth Muscle Cells via Smad3

A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response

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Protein phosphatase magnesium-dependent 1A–mediated inhibition of BMP signaling is independent of Smad dephosphorylation

Cited by 38 publications

References 35 publications

Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling

Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling

Transforming Growth Factor-β1 Represses Bone Morphogenetic Protein–Mediated Smad Signaling in Pulmonary Artery Smooth Muscle Cells via Smad3

A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response

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Transforming Growth Factor-β₁ Represses Bone Morphogenetic Protein–Mediated Smad Signaling in Pulmonary Artery Smooth Muscle Cells via Smad3