Prodomains regulate the synthesis, extracellular localisation and activity of TGF-β superfamily ligands

Harrison, Craig A.; Al-Musawi, Sara L.; Walton, Kelly L.

doi:10.3109/08977194.2011.608666

Cited by 106 publications

(95 citation statements)

References 114 publications

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“…This finding is consistent with the presence of largely latent complexes between BMPs, their prodomains, and extracellular matrix components in the insoluble residual matrix from which BMPs were purified. In agreement with a regulatory role for the prodomain, mutations of secondary PC sites within the prodomain perturb embryonic development in insects and vertebrates, suggesting that prodomains of several BMPs remain associated with GFs after secretion and regulate the distance over which BMPs signal (4)(5)(6)(7). An important role for the prodomain in development is also illustrated by prodomain mutations, including in secondary PC cleavage sites, that cause human diseases (5,7).…”

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confidence: 81%

Structure of bone morphogenetic protein 9 procomplex

Brown

Gao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

219

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Bone morphogenetic proteins (BMPs) belong to the TGF-β family, whose 33 members regulate multiple aspects of morphogenesis. TGF-β family members are secreted as procomplexes containing a small growth factor dimer associated with two larger prodomains. As isolated procomplexes, some members are latent, whereas most are active; what determines these differences is unknown. Here, studies on pro-BMP structures and binding to receptors lead to insights into mechanisms that regulate latency in the TGF-β family and into the functions of their highly divergent prodomains. The observed open-armed, nonlatent conformation of pro-BMP9 and pro-BMP7 contrasts with the cross-armed, latent conformation of pro-TGF-β1. Despite markedly different arm orientations in pro-BMP and pro-TGF-β, the arm domain of the prodomain can similarly associate with the growth factor, whereas prodomain elements N-and C-terminal to the arm associate differently with the growth factor and may compete with one another to regulate latency and stepwise displacement by type I and II receptors. Sequence conservation suggests that pro-BMP9 can adopt both crossarmed and open-armed conformations. We propose that interactors in the matrix stabilize a cross-armed pro-BMP conformation and regulate transition between cross-armed, latent and open-armed, nonlatent pro-BMP conformations.

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mentioning

confidence: 81%

Structure of bone morphogenetic protein 9 procomplex

Brown

Gao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

219

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“…If the BMP4 prodomain has a higher affinity for mature BMP7 than for mature BMP4, this would explain why it remains complexed with mature heterodimers, but not homodimers. Furthermore, because the relative affinities of mature TGFβ family ligands for prodomain versus receptor binding can determine whether a prodomain/growth factor complex is latent or active (36), this might contribute to the inability of the BMP7 prodomain to support active homodimer or heterodimer signaling. BMP heterodimers engage a unique receptor complex (10,34) and it is possible that the relative affinity of this complex for the heterodimeric ligand is sufficient to displace two BMP4 prodomains or one of each prodomain but not two copies of the BMP7 prodomain.…”

Section: Discussionmentioning

confidence: 99%

The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

Neugebauer¹,

Kwon

Kim³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Bone morphogenetic proteins 4 and 7 (BMP4 and BMP7) are morphogens that signal as either homodimers or heterodimers to regulate embryonic development and adult homeostasis. BMP4/7 heterodimers exhibit markedly higher signaling activity than either homodimer, but the mechanism underlying the enhanced activity is unknown. BMPs are synthesized as inactive precursors that dimerize and are then cleaved to generate both the bioactive ligand and prodomain fragments, which lack signaling activity. Our study reveals a previously unknown requirement for the BMP4 prodomain in promoting heterodimer activity. We show that BMP4 and BMP7 precursor proteins preferentially or exclusively form heterodimers when coexpressed in vivo. In addition, we show that the BMP4 prodomain is both necessary and sufficient for generation of stable heterodimeric ligands with enhanced activity and can enable homodimers to signal in a context in which they normally lack activity. Our results suggest that intrinsic properties of the BMP4 prodomain contribute to the relative bioactivities of homodimers versus heterodimers in vivo. These findings have clinical implications for the use of BMPs as regenerative agents for the treatment of bone injury and disease.B one morphogenetic proteins (BMPs) are members of the TGFβ superfamily that were originally isolated as boneinducing morphogens and were subsequently found to play central roles during embryogenesis and in adult homeostasis (1). BMPs are clinically important therapeutic agents that are used to reverse bone loss caused by trauma, disease, and tumor resection (2). Their use as regenerative agents is limited, however, by their short half-life and low specific activity when implanted in vivo. Understanding how BMP activity is regulated is important for the development of more effective therapeutic agents for the treatment of bone injury and disease.BMPs bind to and activate a receptor complex consisting of type I and type II transmembrane serine/threonine kinases. Following ligand binding, activated receptors propagate their signal by phosphorylating one of the SMADs that is specific for the BMP pathway (SMAD1, -5, or -8). The phosphorylated Smads then form heterooligomers with the common Smad, Smad4, and this complex translocates into the nucleus where it binds to BMP response elements and activates transcription of target genes (1).BMPs are classified into subfamilies based on sequence homology. They signal as either homodimers, or as heterodimers from different subfamilies. For example, class I BMPs, which consist of BMP2 and BMP4, can heterodimerize with class II BMPs, consisting of BMP5-8 (3). Heterodimers composed of distinct BMP family members show a higher specific activity than do homodimers of either subunit. Homodimers of BMP2, -4, or -7, for example, can all induce bone formation, but heterodimers of BMP2 plus BMP7, or BMP4 plus BMP7 are significantly more potent (5-to 20-fold) than any of the homodimers in osteogenic differentiation assays (4-6). BMP2/7 and BMP4/7 heterodimers also sho...

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“…In contrast to TGF-b, however, the mature activin dimers are released in an active form that is not inhibited by binding to the pro-peptide. Nevertheless, there is evidence that these dimers still associate with the pro-peptide in the extracellular environment, which is important for their interaction with the extracellular matrix (reviewed by Harrison et al, 2011;Gold and Risbridger, 2012). Four distinct activin genes are present in mammals, encoding the activin subunits bA, bB, bC and bE (Fig.…”

Section: Introductionmentioning

confidence: 99%

The bright and the dark sides of activin in wound healing and cancer

Antsiferova

Werner

2012

Journal of Cell Science

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SummaryActivin was initially described as a protein that stimulates release of follicle stimulating hormone from the pituitary, and it is well known for its important roles in different reproductive functions. In recent years, this multifunctional factor has attracted the attention of researchers in other fields, as new functions of activin in angiogenesis, inflammation, immunity, fibrosis and cancer have been discovered. Studies from our laboratory have identified activin as a crucial regulator of wound healing and skin carcinogenesis. On the one hand, it strongly accelerates the healing process of skin wounds but, on the other hand, it enhances scar formation and the susceptibility to skin tumorigenesis. Finally, results from several laboratories have revealed that activin enhances tumour formation and/ or progression in some other organs, in particular through its effect on the tumour microenvironment, and that it also promotes cancerinduced bone disruption and muscle wasting. These findings provide the basis for the use of activin or its downstream targets for the improvement of impaired wound healing, and of activin antagonists for the prevention and treatment of fibrosis and of malignant tumours that overexpress activin. Here, we summarize the previously described roles of activin in wound healing and scar formation and discuss functional studies that revealed different functions of activin in the pathogenesis of cancer. The relevance of these findings for clinical applications will be highlighted.

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Prodomains regulate the synthesis, extracellular localisation and activity of TGF-β superfamily ligands

Cited by 106 publications

References 114 publications

Structure of bone morphogenetic protein 9 procomplex

Structure of bone morphogenetic protein 9 procomplex

The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

The bright and the dark sides of activin in wound healing and cancer

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