Suppression of BMP-Smad Signaling Axis-Induced Osteoblastic Differentiation by Small C-terminal Domain Phosphatase 1, a Smad Phosphatase

Kokabu, Shoichiro; Ohte, Satoshi; Sasanuma, Hiroyuki; Shin, Masashi; Yoneyama, Katsumi; Murata, Eri; Kanomata, Kazuhiro; Nojima, Junya; Ono, Yusuke; Yoda, Tetsuya; Fukuda, Tsuyoshi; Katagiri, Takenobu

doi:10.1210/me.2010-0305

Cited by 27 publications

(18 citation statements)

References 35 publications

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“…The effects of the SCPs on Smads may therefore depend on a balance between phosphorylation and dephosphorylation at the linker region and the SVS motif. Interestingly, similar to PPM1A, SCP1 suppressed the constitutively active Smad1(DVD)-induced osteoblastic differentiation of C2C12 cells (Kokabu et al , 2011 ). In contrast to PPM1A, however, SCP1 did not change the protein levels of Smads and showed minimal effects on Id1 expression, suggesting that SCP1 may target the downstream effector(s) of the BMP -Smad axis rather than the Smads themselves, at least in this model (Kokabu et al , 2011 ).…”

Section: Roles Of Smad Post-translational Modifications Protein Phospmentioning

confidence: 76%

“…Interestingly, similar to PPM1A, SCP1 suppressed the constitutively active Smad1(DVD)-induced osteoblastic differentiation of C2C12 cells (Kokabu et al , 2011 ). In contrast to PPM1A, however, SCP1 did not change the protein levels of Smads and showed minimal effects on Id1 expression, suggesting that SCP1 may target the downstream effector(s) of the BMP -Smad axis rather than the Smads themselves, at least in this model (Kokabu et al , 2011 ). The phosphorylation of the linker region by Cyclindependent kinase 8/9 has been shown to enhance Smad activity (Alarcon et al , 2009 ), although phosphorylation by MAPK and glycogen synthase kinase 3 (GSK3) suppresses Smad activity ( Figure 5).…”

Section: Roles Of Smad Post-translational Modifications Protein Phospmentioning

confidence: 87%

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The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway

Katagiri

Tsukamoto

2013

Biological Chemistry

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Bone morphogenetic proteins (BMPs) are multifunctional cytokines that belong to the transforming growth factor-β family. BMPs were originally identified based on their unique activity, inducing heterotopic bone formation in skeletal muscle. This unique BMP activity is transduced by specific type I and type II transmembrane kinase receptors. Among the downstream pathways activated by these receptors, the Smad1/5/8 transcription factors appear to play critical roles in BMP activity. Smad1/5/8 transcription factors are phosphorylated at the C-terminal SVS motif by BMP type I receptors and then induce the transcription of early BMP-responsive genes by binding to conserved sequences in their enhancer regions. The linker regions of Smad1/5/8 contain multiple kinase phosphorylation sites, and phosphorylation and dephosphorylation of these sites regulate the transcriptional activity of Smad proteins. Gainof-function mutations in one BMP type I receptor have been identified in patients with fibrodysplasia ossificans progressiva, a rare genetic disorder that is characterized by progressive heterotopic bone formation in the skeletal muscle. The mutant receptors activate the Smad signaling pathway even in the absence of BMPs, therefore novel inhibitors for the BMP receptor -Smad axis are being developed to prevent heterotopic bone formation in fibrodysplasia ossificans progressiva. Taken together, the data in the literature show that the BMP type I receptor -Smad signaling axis is the critical pathway for the unique activity of BMPs and is a potential therapeutic target for pathological conditions caused by inappropriate BMP activity.

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Section: Roles Of Smad Post-translational Modifications Protein Phospmentioning

confidence: 76%

Section: Roles Of Smad Post-translational Modifications Protein Phospmentioning

confidence: 87%

The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway

Katagiri

Tsukamoto

2013

Biological Chemistry

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“…Small C-terminal peptidases can target Smads for dephosphorylation, but do not affect Smad1 protein or Id transcription (14,15). protein phosphatase 1A can also drive Smad degradation independently of the C-terminal SSVS or linker region SMURF sites (15).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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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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“…Mouse C/EBPa (plasmid ID; MmCD00314721), mouse C/EBPb (plasmid ID; MmCD00297423) were provided by DF/HCC DNA Resource Core (BCMP Department 240 Longwood Ave. Boston, MA 02115). Mouse TLE3 (accession number NM_001083927) and Mouse PPARc (accession number NM_011146.3) were obtained by a standard RT-PCR technique using PrimeSTAR HS DNA polymerase (TaKaRa, Ohtsu, Japan) [32] and cloned into pcDNA3.1/V5 (Invitrogen) or a pcDEF3 expression vector [33]. Mouse Runx2 [9] was kindly provided by Dr. Toshihisa Komori (Nagasaki University).…”

Section: Plasmidsmentioning

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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Suppression of BMP-Smad Signaling Axis-Induced Osteoblastic Differentiation by Small C-terminal Domain Phosphatase 1, a Smad Phosphatase

Cited by 27 publications

References 35 publications

The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway

The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway

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

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

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Suppression of BMP-Smad Signaling Axis-Induced Osteoblastic Differentiation by Small C-terminal Domain Phosphatase 1, a Smad Phosphatase

Cited by 27 publications

References 35 publications

The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway

The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway

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

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

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