Mouse Smad8 Phosphorylation Downstream of BMP Receptors ALK-2, ALK-3, and ALK-6 Induces Its Association with Smad4 and Transcriptional Activity

Kawai, Shinji; Faucheu, Chi; Gallea, Sylvie; Spinella-Jaegle, Sylviane; Atfi, Azeddine; Baron, Roland; Roman-Roman, Sergio

doi:10.1006/bbrc.2000.2704

Cited by 56 publications

(34 citation statements)

References 26 publications

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“…The TGF-β type I receptors ALK4, ALK5, and ALK7 are not or are only inefficiently able to do this, which is consistent with the idea that Smad1 is a signaling mediator for BMP signals. Other investigators have suggested the same for Smad8 (23,24). This experiment ( Figure 3C) was performed in HEK 293T cells, which allow a reproducible high level of transgene expression.…”

Section: Figurementioning

confidence: 78%

“…Since Smad8 has been described as a Smad molecule that mediates BMP signals (23)(24)(25), and because the forced expression of full-length Smad8 in C3H10T1/2-BMP2 cells was unable to stimulate BMP2-dependent osteogenesis, we questioned whether Smad8 possesses biological activity or interferes with BMPdependent signalling. In the carboxyterminal end of its MH2 domain, Smad8 harbors an SSVS motif that has the potential to be phosphorylated for Smad activation (23,24). In the mesenchymal progenitor cell line C2C12, however, various types of BMPs activate overexpressed Smad8 only marginally (25).…”

Section: Figurementioning

confidence: 99%

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Neotendon formation induced by manipulation of the Smad8 signalling pathway in mesenchymal stem cells

Hoffmann

Pelled²,

Turgeman³

et al. 2006

Journal of Clinical Investigation

222

166

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Section: Figurementioning

confidence: 78%

Section: Figurementioning

confidence: 99%

Neotendon formation induced by manipulation of the Smad8 signalling pathway in mesenchymal stem cells

Hoffmann

Pelled²,

Turgeman³

et al. 2006

Journal of Clinical Investigation

222

166

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“…However, the specific functional role of Smad8, which displays a high homology with Smad1 and Smad5, is not clear. Smad8 has been shown to be phosphorylated by ALK-2, ALK-3, and ALK-6 and thus acts as a downstream mediator for these receptors (53,76). Moreover, dominant-negative Smad8 was shown to inhibit the increase in alkaline phosphatase activity induced by BMP-2 in mesenchymal C3H10T1/2 cells and C2C12 myoblastic cells, indicating that Smad8 might play a role in this induction (53).…”

Section: Tgf-␤ Receptor Alk-5 Inhibits Maturation and Osteoblastic DImentioning

confidence: 99%

“…Smad8 has been shown to be phosphorylated by ALK-2, ALK-3, and ALK-6 and thus acts as a downstream mediator for these receptors (53,76). Moreover, dominant-negative Smad8 was shown to inhibit the increase in alkaline phosphatase activity induced by BMP-2 in mesenchymal C3H10T1/2 cells and C2C12 myoblastic cells, indicating that Smad8 might play a role in this induction (53). Recently, Aoki et al (16) reported that BMP-4 induces alkaline phosphatase activity equally well in the presence of Smad1, Smad5, and Smad8 in C2C12 cells.…”

Section: Tgf-␤ Receptor Alk-5 Inhibits Maturation and Osteoblastic DImentioning

confidence: 99%

Functions of Transforming Growth Factor-β Family Type I Receptors and Smad Proteins in the Hypertrophic Maturation and Osteoblastic Differentiation of Chondrocytes

Valcourt

Gouttenoire

Moustakas

et al. 2002

Journal of Biological Chemistry

123

103

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We investigated the effects of bone morphogenetic protein (BMP)-2, a member of the transforming growth factor-␤ superfamily, on the regulation of the chondrocyte phenotype, and we identified signaling molecules involved in this regulation. BMP-2 triggers three concomitant responses in mouse primary chondrocytes and chondrocytic MC615 cells. First, BMP-2 stimulates expression or synthesis of type II collagen. Second, BMP-2 induces expression of molecular markers characteristic of pre-and hypertrophic chondrocytes, such as Indian hedgehog, parathyroid hormone/parathyroid hormonerelated peptide receptor, type X collagen, and alkaline phosphatase. Third, BMP-2 induces osteocalcin expression, a specific trait of osteoblasts. Constitutively active forms of transforming growth factor-␤ family type I receptors and Smad proteins were overexpressed to address their role in this process. Activin receptor-like kinase (ALK)-1, ALK-2, ALK-3, and ALK-6 were able to reproduce the hypertrophic maturation of chondrocytes induced by BMP-2. In addition, ALK-2 mimicked further the osteoblastic differentiation of chondrocytes induced by BMP-2. In the presence of BMP-2, Smad1, Smad5, and Smad8 potentiated the hypertrophic maturation of chondrocytes, but failed to induce osteocalcin expression. Smad6 and Smad7 impaired chondrocytic expression and osteoblastic differentiation induced by BMP-2. Thus, our results indicate that Smad-mediated pathways are essential for the regulation of the different steps of chondrocyte and osteoblast differentiation and suggest that additional Smad-independent pathways might be activated by ALK-2.The development of long bones involves first the formation of cartilage primordia, which prefigure the future skeletal elements, and the replacement of the cartilage by bone. The formation of cartilage is initiated by the condensation and differentiation of mesenchymal cells into chondrocytes. This commitment to the skeletal lineage progresses through a switch in gene activation and results in the production of a cartilage matrix, which contains predominantly type II collagen and the proteoglycan aggrecan. During replacement of cartilage by bone through the sequence of events called endochondral ossification, chondrocytes enter a process of maturation, characterized by cellular hypertrophy and onset of type X collagen expression (reviewed in Ref. 1). This is followed by vascular invasion, matrix degradation, and replacement of the cartilage by bone marrow and trabecular bone.Chondrocyte differentiation and maturation is thus a central cellular aspect of skeletal development, and a molecular understanding of skeletogenesis requires an understanding of how expression of the chondrocytic phenotype is regulated. The fate of the skeletal cells and their precursors is controlled by the extracellular matrix, growth factors, hormones, and cytokines. Bone morphogenetic proteins (BMPs) 1 play a particularly important role in skeletal formation. Although BMPs have been shown to have a broad spectrum of action on proliferati...

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“…Binding of BMPs to receptor complexes activates another subset of R-Smads, namely Smad1, Smad5 and Smad8 (Kawai et al, 2000;Meersseman et al, 1997). Unique to the Nodal system is the crucial requirement of a co-receptor from the EGF-CFC family -Cripto and Cryptic (Ding et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Antagonism of Nodal signaling by BMP/Smad5 prevents ectopic primitive streak formation in the mouse amnion

et al. 2012

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SUMMARYThe strength and spatiotemporal activity of Nodal signaling is tightly controlled in early implantation mouse embryos, including by autoregulation and feedback loops, and involves secreted and intracellular antagonists. These control mechanisms, which are established at the extra-embryonic/embryonic interfaces, are essential for anterior-posterior patterning of the epiblast and correct positioning of the primitive streak. Formation of an ectopic primitive streak, or streak expansion, has previously been reported in mutants lacking antagonists that target Nodal signaling. Here, we demonstrate that loss-of-function of a major bone morphogenetic protein (BMP) effector, Smad5, results in formation of an ectopic primitive streak-like structure in mutant amnion accompanied by ectopic Nodal expression. This suggests that BMP/Smad5 signaling contributes to negative regulation of Nodal. In cultured cells, we find that BMP-activated Smad5 antagonizes Nodal signaling by interfering with the Nodal-Smad2/4-Foxh1 autoregulatory pathway through the formation of an unusual BMP4-induced Smad complex containing Smad2 and Smad5. Quantitative expression analysis supports that ectopic Nodal expression in the Smad5 mutant amnion is induced by the Nodal autoregulatory loop and a slow positive-feedback loop. The latter involves BMP4 signaling and also induction of ectopic Wnt3. Ectopic activation of these Nodal feedback loops in the Smad5 mutant amnion results in the eventual formation of an ectopic primitive streak-like structure. We conclude that antagonism of Nodal signaling by BMP/Smad5 signaling prevents primitive streak formation in the amnion of normal mouse embryos.

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Mouse Smad8 Phosphorylation Downstream of BMP Receptors ALK-2, ALK-3, and ALK-6 Induces Its Association with Smad4 and Transcriptional Activity

Cited by 56 publications

References 26 publications

Neotendon formation induced by manipulation of the Smad8 signalling pathway in mesenchymal stem cells

Neotendon formation induced by manipulation of the Smad8 signalling pathway in mesenchymal stem cells

Functions of Transforming Growth Factor-β Family Type I Receptors and Smad Proteins in the Hypertrophic Maturation and Osteoblastic Differentiation of Chondrocytes

Antagonism of Nodal signaling by BMP/Smad5 prevents ectopic primitive streak formation in the mouse amnion

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