Bone morphogenetic proteins with some comments on fibrodysplasia ossificans progressiva and NOGGIN

Cohen, M. Michael

doi:10.1002/ajmg.10289

Cited by 33 publications

(24 citation statements)

References 56 publications

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“…Dpp positional information in multiple target fields requires synergistic signaling between two different BMP receptor-ligand pairs [Podos and Ferguson, 1999]. The heteromeric receptor complex consists of two types of serine-threonine kinases [Cohen, 2002[Cohen, , 2003]. On Dpp ligand binding, the type II receptor (Punt, Put) phosphorylates the type I receptor (Thick veins, Tkv), which activates Mad and Med followed by transcription of target genes.…”

Section: Target Genesmentioning

confidence: 99%

The hedgehog signaling network

Cohen

2003

American J of Med Genetics Pt A

387

230

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In the hedgehog signaling network, mutations result in various phenotypes, including, among others, holoprosencephaly, nevoid basal cell carcinoma syndrome, Pallister-Hall syndrome, Greig cephalopolysyndactyly, Rubinstein-Taybi syndrome, isolated basal cell carcinoma, and medulloblastoma. Active Hedgehog ligand is double lipid modified with a C-terminal cholesterol moiety and an N-terminal palmitate. Transport active Hedgehog from the signaling cell to the responding cell occurs through three mechanisms: 1). formation of multimeric Hedgehog which makes it soluble; 2). function of Dispatched in releasing the lipid-anchored protein from the signaling cell; and 3). movement across the plasma membrane of the responding cell by Tout-velu-dependent synthesis of heparan sulfate proteoglycan. In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling. Patched and Smoothened may shuttle oppositely between the plasma membrane and endocytic vesicles in response to active Hedgehog ligand. In downstream signaling, Cubitus interruptus (Gli proteins in vertebrates), Costal 2, Fused, and Suppressor of Fused form a tetrameric complex. Cubitus interruptus is a bifunctional transcription regulator. In the absence of active Hedgehog ligand, a truncated transcriptional repressor is generated that binds target genes and blocks their transcription. In the presence of active Hedgehog ligand, a full length transcriptional activator binds target genes and upregulates their transcription. Target genes include Wingless (Wnt gene family in vertebrates), Decapentaplegic (Bone Morphogenetic Proteins in vertebrates), and Patched. The upregulation of Patched expression, resulting in Patched protein at the cell membrane, sequesters Hedgehog and limits its spread beyond the cells in which it is produced. Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other. Many more factors that are essential for the hedgehog signaling network are also discussed: Megalin, Rab23, Hip, GAS1, PKA, GSK3, CK1, Slimb, SAP18, and CBP.

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Section: Target Genesmentioning

confidence: 99%

The hedgehog signaling network

Cohen

2003

American J of Med Genetics Pt A

387

230

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“…BMP has previously been reported to play an important role in osteoblast differentiation from progenitor cells [4]. To further investigate the physiological function of PPM1H by regulating Smad1 phosphorylation, we examined the effect of PPM1H on the osteoblastlike differentiation of C2C12 cells.…”

Section: Ppm1h Inhibits Bmp-induced C2c12 Osteoblast-like Differentiamentioning

confidence: 99%

“…With the exception of BMP1, BMPs belong to the transforming growth factor-β (TGF-β) superfamily [3]. Genetic studies have demonstrated that BMPs play important roles in skeletal development, including osteoblast expansion, differentiation, and bone formation [4]. In addition to their functions in skeletal development, BMPs are critical signaling molecules in early embryo development and organogenesis by regulating cell proliferation, differentiation, migration, and apoptosis [5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Specific control of BMP signaling and mesenchymal differentiation by cytoplasmic phosphatase PPM1H

et al. 2014

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Bone morphogenetic proteins (BMPs) belong to the TGF-β superfamily of structurally related signaling proteins that regulate a wide array of cellular functions. The key step in BMP signal transduction is the BMP receptormediated phosphorylation of transcription factors Smad1, 5, and 8 (collectively Smad1/5/8), which leads to the subsequent activation of BMP-induced gene transcription in the nucleus. In this study, we describe the identification and characterization of PPM1H as a novel cytoplasm-localized Smad1/5/8-specific phosphatase. PPM1H directly interacts with Smad1/5/8 through its Smad-binding domain, and dephosphorylates phospho-Smad1/5/8 (P-Smad1/5/8) in the cytoplasm. Ectopic expression of PPM1H attenuates BMP signaling, whereas loss of PPM1H activity or expression greatly enhances BMP-dependent gene regulation and mesenchymal differentiation. In conclusion, this study suggests that PPM1H acts as a gatekeeper to prevent excessive BMP signaling through dephosphorylation and subsequent nuclear exclusion of P-Smad1/5/8 proteins.

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“…This differentiation process is regulated by several cytokines, including bone morphogenetic proteins, transforming growth factor ␤, Wnt, and hedgehog (2)(3)(4)(5). Among them, BMP2 (bone morphogenetic protein 2) is one of the most powerful cytokines that promote differentiation of mesenchymal cells into osteoblasts in vitro and induce bone formation in vivo (2). BMP2 exhibits this osteogenic action by activating Smad signaling and by regulating transcription of osteogenic genes such as ALP, type I collagen, osteocalcin, and bone sialoprotein (Bsp) 2 (6).…”

mentioning

confidence: 99%

“…Among them, BMP2 (bone morphogenetic protein 2) is one of the most powerful cytokines that promote differentiation of mesenchymal cells into osteoblasts in vitro and induce bone formation in vivo (2). BMP2 exhibits this osteogenic action by activating Smad signaling and by regulating transcription of osteogenic genes such as ALP, type I collagen, osteocalcin, and bone sialoprotein (Bsp) 2 (6). Runt-related gene 2 (Runx2)/Core-binding factor 1 (Cbfa1), an essential transcription factor for osteoblast differentiation and bone formation (7) and responsible gene for cleidocranial dysplasia (8), directly regulates the expression of osteocalcin and Bsp (9).…”

mentioning

confidence: 99%

BMP2 Regulates Osterix through Msx2 and Runx2 during Osteoblast Differentiation

Matsubara

Kida

Yamaguchi

et al. 2008

Journal of Biological Chemistry

470

373

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Osterix/Sp7, a member of the Sp1 transcription factor family, plays an essential role in bone formation and osteoblastogenesis. Although Osterix has been shown to be induced by BMP2 in a mesenchymal cell line, the molecular basis of the regulation, expression and function of Osterix during osteoblast differentiation, is not fully understood. Thus we examined the role of BMP2 signaling in the regulation of Osterix using the mesenchymal cell lines C3H10T1/2 and C2C12. Osterix overexpression induced alkaline phosphatase activity and osteocalcin expression in C2C12 cells and stimulated calcification of murine primary osteoblasts. Considering that Runx2 overexpression induces Osterix, these results suggest that Osterix functions as downstream of Runx2. Surprisingly, BMP2 treatment induced Osterix expression and alkaline phosphatase activity in mesenchymal cells derived from Runx2-deficient mice. Furthermore, overexpression of Smad1 and Smad4 upregulated Osterix expression, and an inhibitory Smad, Smad6, markedly suppressed BMP2-induced Osterix expression in the Runx2-deficient cells. Moreover, overexpression of a homeobox gene, Msx2, which is up-regulated by BMP2 and promotes osteoblastic differentiation, induced Osterix expression in the Runx2-deficient cells. Knockdown of Msx2 clearly inhibited induction of Osterix by BMP2 in the Runx2-deficient mesenchymal cells. Interestingly, microarray analyses using the Runx2-deficient cells revealed that the role of Osterix was distinct from that of Runx2. These findings suggest that Osterix is regulated via both Runx2-dependent and -independent mechanisms, and that Osterix controls osteoblast differentiation, at least in part, by regulating the expression of genes not controlled by Runx2.Osteoblasts are differentiated from multipotent mesenchymal cells (1). This differentiation process is regulated by several cytokines, including bone morphogenetic proteins, transforming growth factor ␤, Wnt, and hedgehog (2-5). Among them, BMP2 (bone morphogenetic protein 2) is one of the most powerful cytokines that promote differentiation of mesenchymal cells into osteoblasts in vitro and induce bone formation in vivo (2). BMP2 exhibits this osteogenic action by activating Smad signaling and by regulating transcription of osteogenic genes such as ALP, type I collagen, osteocalcin, and bone sialoprotein (Bsp) 2 (6). Runt-related gene 2 (Runx2)/Core-binding factor 1 (Cbfa1), an essential transcription factor for osteoblast differentiation and bone formation (7) and responsible gene for cleidocranial dysplasia (8), directly regulates the expression of osteocalcin and Bsp (9). BMP2 is known to control the expression and functions of Runx2 through Smad signaling (10 -12). These findings have established the importance of the BMP2-SmadRunx2 axis in osteoblastogenesis.Osterix, an Sp1 transcription family member, is up-regulated by BMP2 during osteoblastic differentiation (13). Osterix has also been reported to inhibit chondrogenesis (14). Mice deficient in the Osterix gene show no bone formation...

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Bone morphogenetic proteins with some comments on fibrodysplasia ossificans progressiva and NOGGIN

Cited by 33 publications

References 56 publications

The hedgehog signaling network

The hedgehog signaling network

Specific control of BMP signaling and mesenchymal differentiation by cytoplasmic phosphatase PPM1H

BMP2 Regulates Osterix through Msx2 and Runx2 during Osteoblast Differentiation

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