scholarly journals The structural basis of TGF-β, bone morphogenetic protein, and activin ligand binding

Reproduction ◽  
2006 ◽  
Vol 132 (2) ◽  
pp. 179-190 ◽  
Author(s):  
S Jack Lin ◽  
Thomas F Lerch ◽  
Robert W Cook ◽  
Theodore S Jardetzky ◽  
Teresa K Woodruff
Keyword(s):  
Signal Transduction ◽  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Structural Basis ◽  
Cellular Processes ◽  
Morphogenetic Protein ◽  
Check Points ◽  
Membrane Level

The transforming growth factor-β (TGF-β) superfamily is a large group of structurally related growth factors that play prominent roles in a variety of cellular processes. The importance and prevalence of TGF-β signaling are also reflected by the complex network of check points that exist along the signaling pathway, including a number of extracellular antagonists and membrane-level signaling modulators. Recently, a number of important TGF-β crystal structures have emerged and given us an unprecedented clarity on several aspects of the signal transduction process. This review will highlight these latest advances and present our current understanding on the mechanisms of specificity and regulation on TGF-β signaling outside the cell.

scholarly journals Molecular and Cellular Mechanisms of Palate Development

2017 ◽  
Vol 96 (11) ◽  
pp. 1184-1191 ◽  
Author(s):  
C. Li ◽  
Y. Lan ◽  
R. Jiang
Keyword(s):  
Growth Factor ◽  
Regulatory Networks ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Mechanisms ◽  
Palate Development ◽  
Palatal Shelf ◽  
Cellular Processes ◽  
Morphogenetic Protein ◽  
Secondary Palate

Development of the mammalian secondary palate involves highly dynamic morphogenetic processes, including outgrowth of palatal shelves from the oral side of the embryonic maxillary prominences, elevation of the initially vertically oriented palatal shelves to the horizontal position above the embryonic tongue, and subsequently adhesion and fusion of the paired palatal shelves at the midline to separate the oral cavity from the nasal cavity. Perturbation of any of these processes could cause cleft palate, a common birth defect that significantly affects patients’ quality of life even after surgical treatment. In addition to identifying a large number of genes required for palate development, recent studies have begun to unravel the extensive cross-regulation of multiple signaling pathways, including Sonic hedgehog, bone morphogenetic protein, fibroblast growth factor, transforming growth factor β, and Wnt signaling, and multiple transcription factors during palatal shelf growth and patterning. Multiple studies also provide new insights into the gene regulatory networks and/or dynamic cellular processes underlying palatal shelf elevation, adhesion, and fusion. Here we summarize major recent advances and integrate the genes and molecular pathways with the cellular and morphogenetic processes of palatal shelf growth, patterning, elevation, adhesion, and fusion.

scholarly journals Structural basis of specific inhibition of extracellular activation of pro- or latent myostatin by the monoclonal antibody SRK-015

2020 ◽  
Vol 295 (16) ◽  
pp. 5404-5418
Author(s):  
Kevin B. Dagbay ◽  
Erin Treece ◽  
Frederick C. Streich ◽  
Justin W. Jackson ◽  
Ryan R. Faucette ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Conformational Changes ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Structural Basis ◽  
Cleavage Sites ◽  
Proteolytic Activation ◽  
Protease Cleavage ◽  
Protease Cleavage Sites

Myostatin (or growth/differentiation factor 8 (GDF8)) is a member of the transforming growth factor β superfamily of growth factors and negatively regulates skeletal muscle growth. Its dysregulation is implicated in muscle wasting diseases. SRK-015 is a clinical-stage mAb that prevents extracellular proteolytic activation of pro- and latent myostatin. Here we used integrated structural and biochemical approaches to elucidate the molecular mechanism of antibody-mediated neutralization of pro-myostatin activation. The crystal structure of pro-myostatin in complex with 29H4-16 Fab, a high-affinity variant of SRK-015, at 2.79 Å resolution revealed that the antibody binds to a conformational epitope in the arm region of the prodomain distant from the proteolytic cleavage sites. This epitope is highly sequence-divergent, having only limited similarity to other closely related members of the transforming growth factor β superfamily. Hydrogen/deuterium exchange MS experiments indicated that antibody binding induces conformational changes in pro- and latent myostatin that span the arm region, the loops contiguous to the protease cleavage sites, and the latency-associated structural elements. Moreover, negative-stain EM with full-length antibodies disclosed a stable, ring-like antigen–antibody structure in which the two Fab arms of a single antibody occupy the two arm regions of the prodomain in the pro- and latent myostatin homodimers, suggesting a 1:1 (antibody:myostatin homodimer) binding stoichiometry. These results suggest that SRK-015 binding stabilizes the latent conformation and limits the accessibility of protease cleavage sites within the prodomain. These findings shed light on approaches that specifically block the extracellular activation of growth factors by targeting their precursor forms.

Metalloproteinase and growth factor interactions: do they play a role in pulmonary fibrosis?

2002 ◽  
Vol 283 (1) ◽  
pp. L1-L11 ◽  
Author(s):  
Margaret K. Winkler ◽  
John L. Fowlkes
Keyword(s):  
Acute Lung Injury ◽  
Growth Factors ◽  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Inflammatory Cells ◽  
Transforming Growth Factor Β ◽  
Target Cells

Chronic lung disease due to interstitial fibrosis can be a consequence of acute lung injury and inflammation. The inflammatory response is mediated through the migration of inflammatory cells, actions of proinflammatory cytokines, and the secretion of matrix-degrading proteinases. After the initial inflammatory insult, successful healing of the lung may occur, or alternatively, dysregulated tissue repair can result in scarring and fibrosis. On the basis of recent insights into the mechanisms underlying acute lung injury and its long-term consequences, data suggest that proteinases, such as the matrix metalloproteinases (MMPs), may not only be involved in the breakdown and remodeling that occurs during the injury but may also cause the release of growth factors and cytokines known to influence growth and differentiation of target cells within the lung. Through the release of and activation of fibrosis-promoting cytokines and growth factors such as transforming growth factor-β1, tumor necrosis factor-α, and insulin-like growth factors by MMPs, we propose that these metalloproteinases may be integral to the initiation and progression of pulmonary fibrosis.

scholarly journals PHYSICAL EXERCISE IN THE PROMOTION OF GENE THERAPY AUXILIARY EFFECT

2021 ◽  
Vol 27 (8) ◽  
pp. 779-782
Author(s):  
Wei Shen ◽  
Xiaojun Liang
Keyword(s):  
Gene Therapy ◽  
Growth Factors ◽  
Growth Factor ◽  
Physical Exercise ◽  
Fracture Healing ◽  
Bone Morphogenetic Protein ◽  
Bone Growth ◽  
Transforming Growth Factor ◽  
Transforming Growth Factors ◽  
Morphogenetic Protein

ABSTRACT Introduction: In recent years, genetic engineering has made outstanding contributions to sports, and it has played a huge role in promoting the development of sports-related fields. Objective: We analyze the tissue source of bone growth and healing by studying the role of bone morphogenetic protein and transforming growth factors in fracture injuries caused by sports. Methods: We established a human fracture model to express the shape and content of bone morphogenetic protein and transforming growth factor during fracture healing. Results: In the fracture healing stage caused by different sports, the expression levels of the two genes are different. Bone morphogenetic protein has a high content in the osteogenesis stage of the membrane, while transforming growth factor is high in the cartilage ossification stage. Conclusion: Gene therapy for fractures caused by physical exercise has certain advantages. Osteoblasts and chondrocytes are involved in the synthesis of transforming growth factors. Level of evidence II; Therapeutic studies - investigation of treatment results.

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