Opposing effects of Wnt and MAPK on BMP/Smad signal duration

Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
Developmental Cell (Impact Factor: 9.71). 01/2008; 13(6):755-6. DOI: 10.1016/j.devcel.2007.11.006
Source: PubMed


Signaling downstream of BMP receptors relies on activated nuclear Smad proteins. Recent studies, one of which is published in the November 30 issue of Cell, shed light on a mechanism that balances inputs from both activated MAPK and Wnt pathways to regulate the proteasomal degradation of Smad1 and thus modulate the extent of BMP signaling.

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Available from: Esther M Verheyen,
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    • "Smad4; the nuclear export signal (DNES); the central linker region (DLinker), which contains residues targeted for posttranslational modifications (Verheyen, 2007); and the MH2 domain (DMH2), which mediates direct protein interactions with R-Smads. The NES was spared in the MH1 deletion mutant. "
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    ABSTRACT: Canonical Wnt/β-catenin (cWnt) signaling regulates osteoblast proliferation and differentiation to enhance bone formation. We previously reported that osteogenic action of β-catenin is dependent on BMP signaling. Here, we further examined interactions between cWnt and BMP in bone. In osteoprogenitors stimulated with BMP2, β-catenin localizes to the nucleus, physically interacts with Smad4, and is recruited to DNA-binding transcription complexes containing Smad4, R-Smads1/5, and TCF4. Furthermore, Tcf/Lef-dependent transcription, Ccnd1 expression, and proliferation all increase when Smad4, 1, or 5 levels are low, whereas TCF/Lef activities decrease when Smad4 expression is high. The ability of Smad4 to antagonize transcription of Ccnd1 is dependent on DNA-binding activity; Smad4-dependent transcription is not required. In mice, conditional deletion of Smad4 in Osterix(+) cells increases mitosis of cells on trabecular bone surfaces as well as in primary osteoblast cultures from adult bone marrow and neonatal calvaria. By contrast, ablation of Smad4 delays differentiation and matrix mineralization by primary osteoblasts in response to Wnt3a, indicating that loss of Smad4 perturbs the balance between proliferation and differentiation in osteoprogenitors. We propose that Smad4 and Tcf/Lef transcription complexes compete for β-catenin, thus restraining Wnt/β-catenin-dependent proliferative signals while favoring the matrix synthesizing activity of osteoblasts.
    Journal of Cell Science 10/2013; 126(24). DOI:10.1242/jcs.132233 · 5.43 Impact Factor
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    • "Smad1, 5, and 8 (Smad1/5/8) are classic mediators for BMPs osteoinductive signaling. It has been reported that candidate phosphorylated sites for MAPKs are existed in Smad1/5/8 proteins [57]. Moreover, MAPKs activation by BMPs has shown to influence Smads signaling in different cell models [9], [10], [26], [39]. "
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    ABSTRACT: Although previous studies have demonstrated that BMP9 is highly capable of inducing osteogenic differentiation and bone formation, the precise molecular mechanism involved remains to be fully elucidated. In this current study, we explore the possible involvement and detail effects of p38 and ERK1/2 MAPKs on BMP9-induced osteogenic differentiation of mesenchymal progenitor cell (MPCs). We find that BMP9 simultaneously stimulates the activation of p38 and ERK1/2 in MPCs. BMP9-induced early osteogenic marker, such as alkaline phosphatase (ALP), and late osteogenic markers, such as matrix mineralization and osteocalcin (OC) are inhibited by p38 inhibitor SB203580, whereas enhanced by ERK1/2 inhibitor PD98059. BMP9-induced activation of Runx2 and Smads signaling are reduced by SB203580, and yet increased by PD98059 in MPCs. The in vitro effects of inhibitors are reproduced with adenoviruses expressing siRNA targeted p38 and ERK1/2, respectively. Using mouse calvarial organ culture and subcutaneous MPCs implantation, we find that inhibition of p38 activity leads to significant decrease in BMP9-induced osteogenic differentiation and bone formation, however, blockage of ERK1/2 results in effective increase in BMP9-indcued osteogenic differentiation in vivo. Together, our results reveal that p38 and ERK1/2 MAPKs are activated in BMP9-induced osteogenic differentiation of MPCs. What is most noteworthy, however, is that p38 and ERK1/2 act in opposition to regulate BMP9-induced osteogenic differentiation of MPCs.
    PLoS ONE 08/2012; 7(8):e43383. DOI:10.1371/journal.pone.0043383 · 3.23 Impact Factor
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    • "Smad ubiquitination regulatory factor 1 (Smurf1) recognizes the doubly phosphorylated linker region of Smad1 and polyubiquitinates (Ub) it (4), thus targeting Smad1 for degradation by the proteasome (5). This figure is modified from Ref. [21]. residues have been substituted by aspartic acids (Fig. 4A). "
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    ABSTRACT: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily and stimulate the osteoblast differentiation of various types of cells. Smads play central roles downstream of BMP signaling. Receptor-regulated Smads (R-Smads) are phosphorylated by BMP receptors on 2 serine residues in the Ser-X-Ser (SXS) motif at the C terminus. Phosphorylated R-Smads form heteromeric complexes with Smad4 and directly activate the transcription of BMP-responsive genes such as Id1. In contrast, the phosphorylation of a linker region of R-Smads by mitogen-activated protein kinases suppresses their translocation to the nucleus and thus represses their transcriptional activity. Recently, distinct types of phosphatases, i.e., small C-terminal domain phosphatases (SCPs) and protein phosphatase magnesium-dependent 1A (PPM1A), have been identified as enzymes that suppress BMP activity by dephosphorylating the C-terminal SXS motifs in Smads. In this review, we focus on these Smad phosphatases and the role of the phosphorylation and dephosphorylation of Smad by introducing our own studies. To determine the role of the phosphorylation and dephosphorylation of Smad1, we used a constitutively active Smad1 mutant expression plasmid, Smad1 (DVD), in which the C-terminal serine residues have been substituted by aspartic acids. PPM1A and SCP1 suppressed the activity of Smad1 (DVD). PPM1A suppressed the osteoblast differentiation induced by BMPs by decreasing Smad protein levels. In contrast, SCP1 did not reduce Smad protein levels but suppressed osteoblast differentiation to target the downstream effectors of Smad, especially Runx2. In conclusion, SCP1 and PPM1A suppress the osteoblast differentiation induced by BMPs independent of Smad dephosphorylation.
    Journal of Oral Biosciences 05/2012; 54(2):73–78. DOI:10.1016/j.job.2012.02.003
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