The pro‐form of BMP‐2 interferes with BMP‐2 signalling by competing with BMP‐2 for IA receptor binding

Hauburger, Anja; Einem, Sabrina von; Schwaerzer, Gerburg K.; Buttstedt, Anja; Zebisch, M.; Schräml, Michael; Hortschansky, Peter; Knaus, Petra; Schwarz, Elisabeth

doi:10.1111/j.1742-4658.2009.07361.x

Cited by 35 publications

(29 citation statements)

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“…The type II receptors ActRIIA, ActRIIB, and BMPRII compete with the pro-domain for binding to the growth factor resulting in a stepwise prodomain displacement (26). The partially latent BMP2⅐pro-domain complex was shown to bind to type I receptor BMPRIA but not to type II receptor BMPRII (27). The pro-domain is FIGURE 7.…”

Section: Discussionmentioning

confidence: 99%

Rapid Activation of Bone Morphogenic Protein 9 by Receptor-mediated Displacement of Pro-domains

Kienast

Jucknischke

Scheiblich

et al. 2016

Journal of Biological Chemistry

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By non-covalent association after proteolytic cleavage, the pro-domains modulate the activities of the mature growth factor domains across the transforming growth factor-␤ family. In the case of bone morphogenic protein 9 (BMP9), however, the pro-domains do not inhibit the bioactivity of the growth factor, and the BMP9⅐pro-domain complexes have equivalent biological activities as the BMP9 mature ligand dimers. By using realtime surface plasmon resonance, we could demonstrate that either binding of pro-domain-complexed BMP9 to type I receptor activin receptor-like kinase 1 (ALK1), type II receptors, coreceptor endoglin, or to mature BMP9 domain targeting antibodies leads to immediate and complete displacement of the pro-domains from the complex. Vice versa, pro-domain binding by an anti-pro-domain antibody results in release of the mature BMP9 growth factor. Based on these findings, we adjusted ELISA assays to measure the protein levels of different BMP9 variants. Although mature BMP9 and inactive precursor BMP9 protein were directly detectable by ELISA, BMP9⅐pro-domain complex could only be measured indirectly as dissociated fragments due to displacement of mature growth factor and prodomains after antibody binding. Our studies provide a model in which BMP9 can be readily activated upon getting into contact with its receptors. This increases the understanding of the underlying biology of BMP9 activation and also provides guidance for ELISA development for the detection of circulating BMP9 variants.Bone morphogenic protein 9 (BMP9 2 ; also known as growth and differentiation factor 2 (GDF2)), is a member of the transforming growth factor ␤ (TGF␤) superfamily. BMP9 is constitutively expressed in liver and secreted into the circulation at active concentrations (1). Circulating BMP9 is a potent biological effector signaling through type I receptor activin-receptorlike kinase 1 (ALK1) in endothelial cells, thereby maintaining vascular homeostasis (2, 3). BMP9 and ALK1 are required for properly organized blood and lymphatic vascular development (4 -6). Human mutations in ALK1 lead to a genetic vascular disorder known as hereditary hemorrhagic telangiectasia (7). Recently, mutations in BMP9 have been identified in individuals with a vascular disorder phenotypically overlapping with hereditary hemorrhagic telangiectasia (8). BMP9 was also discovered to function as a neurotropic factor, potently inducing and maintaining the cholinergic phenotype in the central nervous system (9), and is also the most potent BMP for inducing osteogenic, and to a lesser extent adipogenic and chondrogenic differentiation (10, 11). Osteogenic signaling requires both ALK1 and the low affinity type I receptor ALK2 (12). Type II receptors activin receptor IIA and IIB (ActRIIA and ActRIIB) and BMP receptor II (BMPRII) have also been implicated in ALK1/BMP9 signaling (13). Moreover, endoglin (ENG) has been identified as a co-receptor that can increase BMP9/ALK1 signaling (3,14). This is reflected in a model where ENG and ALK1 act together to bind...

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Section: Discussionmentioning

confidence: 99%

Rapid Activation of Bone Morphogenic Protein 9 by Receptor-mediated Displacement of Pro-domains

Kienast

Jucknischke

Scheiblich

et al. 2016

Journal of Biological Chemistry

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“…For a long time it was assumed that processing of pro-BMPs would take place in the Golgi and that only the processed forms without the pro-domains would be secreted. Association of the pro-domain with the mature growth factor can bind to the extracellular domain of BMPRIA (46). Furthermore, it is known from the literature that, pro-BMP-2 shows no binding characteristics to the extracellular domain of BMPRII (46).…”

Section: Discussionmentioning

confidence: 99%

“…Association of the pro-domain with the mature growth factor can bind to the extracellular domain of BMPRIA (46). Furthermore, it is known from the literature that, pro-BMP-2 shows no binding characteristics to the extracellular domain of BMPRII (46). It is still an open question whether all of the BMP-2 is secreted in its cleaved mature form or if some is secreted as a pro-form.…”

Section: Discussionmentioning

confidence: 99%

The Factor VII-activating Protease (FSAP) Enhances the Activity of Bone Morphogenetic Protein-2 (BMP-2)

Roedel

Schwarz

Kanse

2013

Journal of Biological Chemistry

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Background: Polymorphisms in the gene encoding for Factor VII-activating protease (FSAP) are a risk factor for atherosclerosis and vascular calcification. Results: FSAP mediates proteolytic cleavage and activation of bone morphogenetic protein-2 (BMP-2). Conclusion: FSAP regulates BMP-2-dependent proliferation and osteogenic differentiation of several cell types. Significance: Activation of BMP-2 by FSAP provides a novel mechanistic insight into the actions of FSAP in remodelingassociated diseases.

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“…Studies with the purified pro-form of BMP2 showed that the presence of the proregion inhibits binding to BMP receptor II, while not affecting binding to BMP receptor type I (Hauburger et al, 2009). Limited proteolysis of the proregions and/or pro-forms of BMP2, GDF5 and the Drosophila orthologue of BMP2, decapentaplegic (dpp), led to the identification of protease-resistant sub domains within the proregions (Kuhfahl et al, 2011).…”

Section: The Functionally Versatile Bmp Proregionsmentioning

confidence: 99%

Cystine knot growth factors and their functionally versatile proregions

Schwarz

2017

Biological Chemistry

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Abstract:The cystine knot disulfide pattern has been found to be widespread in nature, since it has been detected in proteins from plants, marine snails, spiders and mammals. Cystine knot proteins are secreted proteins. Their functions range from defense mechanisms as toxins, e.g. ion channel or enzyme inhibitors, to hormones, blood factors and growth factors. Cystine knot proteins can be divided into two superordinate groups. (i) The cystine knot peptides, also referred to -with other non-cystine knot proteins -as knottins, with linear and cyclic polypeptide chains. (ii) The cystine knot growth factor family, which is in the focus of this article. The disulfide ring structure of the cystine knot peptides is made up by the half-cystines 1-4 and 2-5, and the threading disulfide bond is formed by the half-cystines, 3-6. In the growth factor group, the disulfides of half-cystines 1 and 4 pass the ring structure formed by the half-cystines 2-5 and 3-6. In this review, special emphasis will be devoted to the growth factor cystine knot proteins and their proregions. The latter have shifted into the focus of scientific interest as their important biological roles are just to be unravelled.

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The pro‐form of BMP‐2 interferes with BMP‐2 signalling by competing with BMP‐2 for IA receptor binding

Cited by 35 publications

References 50 publications

Rapid Activation of Bone Morphogenic Protein 9 by Receptor-mediated Displacement of Pro-domains

Rapid Activation of Bone Morphogenic Protein 9 by Receptor-mediated Displacement of Pro-domains

The Factor VII-activating Protease (FSAP) Enhances the Activity of Bone Morphogenetic Protein-2 (BMP-2)

Cystine knot growth factors and their functionally versatile proregions

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