Electrostatics and N-glycan-mediated membrane tethering of SCUBE1 is critical for promoting bone morphogenetic protein signalling

2016 ◽  
Vol 473 (5) ◽  
pp. 661-672 ◽  
Author(s):  
Wei-Ju Liao ◽  
Ku-Chi Tsao ◽  
Ruey-Bing Yang
Keyword(s):  
Bone Morphogenetic Protein ◽  
Membrane Localization ◽  
Bone Morphogenetic Protein Signalling ◽  
Morphogenetic Protein ◽  
Membrane Tethering ◽  
Bmp Signalling

We investigated the membrane-associating mechanisms of SCUBE1 (S1), a BMP co-receptor. Electrostatics and glycan-mediated membrane localization of S1 is essential for promoting BMP signalling and N-glycosylation is required for its function in zebrafish.

scholarly journals USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling

Open Biology ◽  
2014 ◽  
Vol 4 (5) ◽  
pp. 140065 ◽  
Author(s):  
Lina Herhaus ◽  
Mazin A. Al-Salihi ◽  
Kevin S. Dingwell ◽  
Timothy D. Cummins ◽  
Lize Wasmus ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Osteoblast Differentiation ◽  
Target Genes ◽  
Bone Morphogenetic Protein Signalling ◽  
Morphogenetic Protein ◽  
Bmp Pathway ◽  
Bmp Signalling ◽  
Myoblast Cells ◽  
Mouse Myoblast ◽  
Transcriptional Target

Protein kinase ALK3/BMPR1A mediates bone morphogenetic protein (BMP) signalling through phosphorylation and activation of SMADs 1/5/8. SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin-mediated degradation. Here, we identify a deubiquitylating enzyme USP15 as an interactor of SMAD6 and ALK3. We show that USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3. RNAi -mediated depletion of USP15 increases ALK3 K48-linked polyubiquitylation, and reduces both BMP-induced SMAD1 phosphorylation and transcription of BMP target genes. We also show that loss of USP15 expression from mouse myoblast cells inhibits BMP-induced osteoblast differentiation. Furthermore, USP15 modulates BMP-induced phosphorylation of SMAD1 and transcription during Xenopus embryogenesis.

scholarly journals Single nucleotide polymorphism of bone morphogenetic protein 4 gene: A risk factor of non-syndromic cleft lip with or without palate

2015 ◽  
Vol 48 (02) ◽  
pp. 159-164 ◽  
Author(s):  
Sathyaprasad Savitha ◽  
S. M. Sharma ◽  
Shetty Veena ◽  
R. Rekha
Keyword(s):  
Bone Morphogenetic Protein ◽  
Cleft Lip ◽  
Paediatric Population ◽  
Single Nucleotide ◽  
Morphogenetic Protein ◽  
Increased Risk ◽  
Polymerase Chain ◽  
Bmp Signalling ◽  
Control Study

ABSTRACT Background: The bone morphogenetic protein (BMP) signalling pathway is crucial in a number of developmental processes and is critical in the formation of variety of craniofacial elements including cranial neural crest, facial primordium, tooth, lip and palate. It is an important mediator in regulation of lip and palate fusion, cartilage and bone formation. Aim: To study the role of mutation of BMP4 genes in the aetiology of non-syndromic cleft lip with or without palate (NSCL ± P) and identify it directly from human analyses. Materials and Methods: A case-control study was done to evaluate whether BMP4T538C polymorphism, resulting in an amino acid change of Val=Ala (V152A) in the polypeptide, is associated with NSCL ± P in an Indian paediatric population. Genotypes of 100 patients with NSCL ± P and 100 controls (in whom absence of CL ± P was confirmed in three generations) were detected using a polymerase chain reaction-restriction fragment length polymorphism strategy. Logistic regression was performed to evaluate allele and genotype association with NSCLP. Results: Results showed significant association between homozygous CC genotype with CL ± P (odds ratio [OR]-5.59 and 95% confidence interval [CI] = 2.85-10.99). The 538C allele carriers showed an increased risk of NSCL ± P as compared with 538 T allele (OR - 4.2% CI = 2.75-6.41). Conclusion: This study suggests an association between SNP of BMP4 gene among carriers of the C allele and increased risk for NSCLP in an Indian Population. Further studies on this aspect can scale large heights in preventive strategies for NSCLP that may soon become a reality.

scholarly journals Regulation of bone morphogenetic protein signalling and cranial osteogenesis by Gpc1 and Gpc3

Bone ◽  
2013 ◽  
Vol 55 (2) ◽  
pp. 367-376 ◽  
Author(s):  
Prem P. Dwivedi ◽  
Randall H. Grose ◽  
Jorge Filmus ◽  
Charles S.T. Hii ◽  
Cory J. Xian ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Bone Morphogenetic Protein Signalling ◽  
Morphogenetic Protein

scholarly journals MicroRNA-186 improves fracture healing through activating the bone morphogenetic protein signalling pathway by inhibiting SMAD6 in a mouse model of femoral fracture

2019 ◽  
Vol 8 (11) ◽  
pp. 550-562 ◽  
Author(s):  
C. Wang ◽  
G-F. Zheng ◽  
X-F. Xu
Keyword(s):  
Mouse Model ◽  
Fracture Healing ◽  
Bone Morphogenetic Protein ◽  
Femoral Fracture ◽  
Maximum Load ◽  
Bone Volume ◽  
Signalling Pathway ◽  
Protein Levels ◽  
Morphogenetic Protein ◽  
Bmp Signalling

Objectives MicroRNAs (miRNAs) have been reported as key regulators of bone formation, signalling, and repair. Fracture healing is a proliferative physiological process where the body facilitates the repair of a bone fracture. The aim of our study was to explore the effects of microRNA-186 (miR-186) on fracture healing through the bone morphogenetic protein (BMP) signalling pathway by binding to Smad family member 6 (SMAD6) in a mouse model of femoral fracture. Methods Microarray analysis was adopted to identify the regulatory miR of SMAD6. 3D micro-CT was performed to assess the bone volume (BV), bone volume fraction (BVF, BV/TV), and bone mineral density (BMD), followed by a biomechanical test for maximum load, maximum radial degrees, elastic radial degrees, and rigidity of the femur. The positive expression of SMAD6 in fracture tissues was measured. Moreover, the miR-186 level, messenger RNA (mRNA) level, and protein levels of SMAD6, BMP-2, and BMP-7 were examined. Results MicroRNA-186 was predicted to regulate SMAD6. Furthermore, SMAD6 was verified as a target gene of miR-186. Overexpressed miR-186 and SMAD6 silencing resulted in increased callus formation, BMD and BV/TV, as well as maximum load, maximum radial degrees, elastic radial degrees, and rigidity of the femur. In addition, the mRNA and protein levels of SMAD6 were decreased, while BMP-2 and BMP-7 levels were elevated in response to upregulated miR-186 and SMAD6 silencing. Conclusion In conclusion, the study indicated that miR-186 could activate the BMP signalling pathway to promote fracture healing by inhibiting SMAD6 in a mouse model of femoral fracture. Cite this article: Bone Joint Res 2019;8:550–562.

scholarly journals Blockage of bone morphogenetic protein signalling counteracts hypertrophy in a human osteoarthritic micro-cartilage model

2020 ◽  
Vol 133 (23) ◽  
pp. jcs249094 ◽  
Author(s):  
Shikha Chawla ◽  
Majoska H. M. Berkelaar ◽  
Boris Dasen ◽  
Christine Halleux ◽  
Sabine Guth-Gundel ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Selective Inhibition ◽  
Type I ◽  
Mesenchymal Progenitors ◽  
Morphogenetic Protein ◽  
Cartilage Extracellular Matrix ◽  
Embryonic Cartilage ◽  
Oa Chondrocytes ◽  
Bmp Signalling

ABSTRACTBone morphogenetic protein (BMP) signalling plays a significant role during embryonic cartilage development and has been associated with osteoarthritis (OA) pathogenesis, being in both cases involved in triggering hypertrophy. Inspired by recent findings that BMP inhibition counteracts hypertrophic differentiation of human mesenchymal progenitors, we hypothesized that selective inhibition of BMP signalling would mitigate hypertrophic features in OA cartilage. First, a 3D in vitro OA micro-cartilage model was established using minimally expanded OA chondrocytes that was reproducibly able to capture OA-like hypertrophic features. BMP signalling was then restricted by means of two BMP receptor type I inhibitors, resulting in reduction of OA hypertrophic traits while maintaining synthesis of cartilage extracellular matrix. Our findings open potential pharmacological strategies for counteracting cartilage hypertrophy in OA and support the broader perspective that key signalling pathways known from developmental processes can guide the understanding, and possibly the mitigation, of adult pathological features.

Role of Goosecoid, Xnot and Wnt antagonists in the maintenance of the notochord genetic programme in Xenopus gastrulae

Development ◽  
2001 ◽  
Vol 128 (19) ◽  
pp. 3783-3793 ◽  
Author(s):  
Hitoyoshi Yasuo ◽  
Patrick Lemaire
Keyword(s):  
Bone Morphogenetic Protein ◽  
Neural Tube ◽  
Wnt Pathway ◽  
Transcriptional Repressor ◽  
Ventral Side ◽  
Morphogenetic Protein ◽  
Bmp Signalling ◽  
Genetic Programme ◽  
Shed Light

The Xenopus trunk organiser recruits neighbouring tissues into secondary trunk axial and paraxial structures and itself differentiates into notochord. The inductive properties of the trunk organiser are thought to be mediated by the secretion of bone morphogenetic protein (BMP) antagonists. Ectopic repression of BMP signals on the ventral side is sufficient to mimic the inductive properties of the trunk organiser. Resultant secondary trunks contain somite and neural tube, but no notochord. We show that inhibition of BMP signalling is sufficient for the initiation of the trunk organiser genetic programme at the onset of gastrulation. During late gastrulation, however, this programme is lost, due to an invasion of secreted Wnts from neighbouring tissues. Maintenance of this programme requires co-repression of BMP and Wnt signalling within the presumptive notochord region. To shed light on the molecular cascade that leads to the repression of the Wnt pathway, we looked for individual organiser genes whose overexpression could complement the inhibition of BMP signalling to promote notochord formation in the secondary trunks. Two genes, gsc and Xnot, were thus identified and shown to act in different ways. Xnot acts as a transcriptional repressor within the mesodermal region. Gsc acts in deeper vegetal cells, where it regulates Frzb expression to maintain Xnot expression in the neighbouring notochord territory. These results suggest that, during gastrulation, the necessary repression of Wnt/β-catenin signalling in notochord precursors is achieved by the action of secreted inhibitors, such as Frzb, emitted by gsc-expressing dorsal vegetal cells.

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