Bone morphogenetic protein receptors and signal transduction

Miyazono, Kohei; Kamiya, Yuto; Morikawa, Masato

doi:10.1093/jb/mvp148

Cited by 883 publications

(941 citation statements)

References 129 publications

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“…The entire hind limb was analyzed for cells responding to the BMP2 at 1 day after the initial injection. The results of immunostaining using an antibody that detects the complex of phosphorylated SMADs 1, 5, and 8 and therefore detects only signaling through receptors for bone morphogenetic proteins [19] showed a dose-dependent response (Figure 1A). The number of positive cells per 10X field was determined by counting five fields on two slides prepared from the limb of each of the four mice that received a given dose.…”

Section: Resultsmentioning

confidence: 99%

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Olmsted-Davis

Salisbury²,

Hoang³

et al. 2017

Stem Cells Translational Medicine

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Studies presented here, using a murine model of bone morphogenetic protein type 2 (BMP2)-induced HO show that the protein initiates HO by signaling through progenitors in the endoneurium of peripheral nerves. In the mouse, these cells were identified in the endoneurium one day after BMP2 induction using antibody against phosphoSMAD (PS) 1, 5, and 8. Studies conducted in a tracking mouse that contains a tamoxifen-regulated Wnt1-Cre recombinase crossed with a td Tomato red (TR) reporter (Wnt1CreErt:Ai9Tm) confirmed their neural origin. In this model both BMP2 induction and tamoxifen are absolutely required to induce TR. SP7+(osterix+)TR+ cells were found in the endoneurium on day 1 and associated with bone on day 7. Quantification of TR+ and TR− cells isolated by FACS showed that all SP7+ cells were found in the TR+ population, whereas only about 80 percent of the TR+ cells expressed SP7. Pre-chondrocytes (Sox 9+) and transient brown fat (tBAT, UCP1+) also co-expressed TR, suggesting that the progenitor in nerves is multi-potential. The endoneurium of human nerves near the site of HO contained many PS+ cells, and SP7+ cells were found in nerves and on bone in tissue from patients with HO. Control tissues and nerves did not contain these PS+ and SP7+ cells. Some osteoblasts on bone from patients with HO were positive for PS, suggesting the continued presence of BMP during bone formation. The data suggests that the progenitors for HO are derived from the endoneurium in both the mouse model of HO and in humans with HO.

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Section: Resultsmentioning

confidence: 99%

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Olmsted-Davis

Salisbury²,

Hoang³

et al. 2017

Stem Cells Translational Medicine

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“…BMP2, BMP4 and BMP5, BMP6, BMP7 form two subgroups that have been extensively studied (1). They mediate their function by binding to two molecules of type 1 (BMPR1 a , BMPR1 b , or ACVR1) and two molecules of type 2 (BMPR2, ACVRL1, ActRII, or ActRII B ) serine/threonine kinase receptors (2). Depending on the presence or absence of preformed BMPR complexes, the signaling is mediated via the SMAD family of transcription factors following a defined canonical pathway or by less defined noncanonical intracellular effectors (3,4).…”

Section: Introductionmentioning

confidence: 99%

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

Calpe

Wagner

Khattabi³

et al. 2015

Molecular Cancer Therapeutics

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Bone morphogenetic proteins (BMP) have important but distinct roles in tissue homeostasis and disease, including carcinogenesis and tumor progression. A large number of BMP inhibitors are available to study BMP function; however, as most of these antagonists are promiscuous, evaluating specific effects of individual BMPs is not feasible. Because the oncogenic role of the different BMPs varies for each neoplasm, highly selective BMP inhibitors are required. Here, we describe the generation of three types of llama-derived heavy chain variable domains (VHH) that selectively bind to either BMP4, to BMP2 and 4, or to BMP2, 4, 5, and 6. These generated VHHs have high affinity to their targets and are able to inhibit BMP signaling. Epitope binning and docking modeling have shed light into the basis for their BMP specificity. As opposed to the wide structural reach of natural inhibitors, these small molecules target the grooves and pockets of BMPs involved in receptor binding. In organoid experiments, specific inhibition of BMP4 does not affect the activation of normal stem cells. Furthermore, in vitro inhibition of cancer-derived BMP4 noncanonical signals results in an increase of chemosensitivity in a colorectal cancer cell line. Therefore, because of their high specificity and low off-target effects, these VHHs could represent a therapeutic alternative for BMP4 þ malignancies.

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“…Members of the transforming growth factor (TGF)-β family, including TGF-β, activin, nodal and bone morphogenetic proteins (BMPs), are multifunctional cytokines that regulate a wide range of cellular responses, such as cellular proliferation, adhesion and differentiation, haematopoiesis, inflammation, wound repair and skeletal development (1). BMPs were identified based on their ability to promote ectopic cartilage and bone formation (2).…”

Section: Introductionmentioning

confidence: 99%

“…BMPs were identified based on their ability to promote ectopic cartilage and bone formation (2). BMPs function through conserved type I and type II transmembrane receptors and Smad-dependent and -independent pathways, to regulate a range of biological processes in a highly context-dependent manner (1,(3)(4)(5). Disruption of these pathways can lead to various diseases including cancer (6).…”

Section: Introductionmentioning

confidence: 99%

Induction of estrogen receptor α-36 expression by bone morphogenetic protein 2 in breast cancer cell lines

Wang

Huang

Baowei

et al. 2012

Molecular Medicine Reports

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Abstract. The expression of estrogen receptor-α (ERα) is one of the most important diagnostic and prognostic factors of breast cancer. Recently, ERα-36 has been identified as a novel variant of ER-α. ERα-36 lacks intrinsic transcription activity and mainly mediates non-genomic estrogen signaling. Bone morphogenetic proteins (BMPs) are recognized as key factors during the control of cell fate and cancer development. However, the correlation between BMP and the ER signaling pathway remains unclear. In this study, we show that BMP2, a member of the BMP family, is a novel inducer of ERα-36 expression in breast cancer cells. As shown by western blot assays, the upregulation of ERα-36 by BMP2 was significant. In MDA-MB-231 cells which are ERα-66-negative, BMP2 was able to induce the expression of ERα-36 in a dose-dependent manner, and the RNA interference assay indicated a correlation between BMP2 and ERα-36 expression. BMP2 inhibited the growth of MCF-7 and MDA-MB-231 cells; however, the inhibitory effect was antagonized by tamoxifen, suggesting that the ER signal was involved. The growth of MDA-MB-231 cells was stimulated by 17-β-estradiol (E2) after BMP2 induction, even though the cells were previously insensitive to E2. These results suggest that BMP2 induces ERα-36 expression and alters tumor resistance to endocrine therapy by changing the expression profile of ERs.

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Bone morphogenetic protein receptors and signal transduction

Cited by 883 publications

References 129 publications

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

Induction of estrogen receptor α-36 expression by bone morphogenetic protein 2 in breast cancer cell lines

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