scholarly journals Insight into Molecular Mechanism for Activin A-Induced Bone Morphogenetic Protein Signaling

2020 ◽  
Vol 21 (18) ◽  
pp. 6498
Author(s):  
Chen Xie ◽  
Wenjuan Jiang ◽  
Jerome J. Lacroix ◽  
Yun Luo ◽  
Jijun Hao
Keyword(s):  
Bone Morphogenetic Protein ◽  
Molecular Mechanism ◽  
Activin A ◽  
Bmp Signaling ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Type Ii ◽  
Signaling Complex ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Activins transduce the TGF-β pathway through a heteromeric signaling complex consisting of type I and type II receptors, and activins also inhibit bone morphogenetic protein (BMP) signaling mediated by type I receptor ALK2. Recent studies indicated that activin A cross-activates the BMP pathway through ALK2R206H, a mutation associated with Fibrodysplasia Ossificans Progressiva (FOP). How activin A inhibits ALK2WT-mediated BMP signaling but activates ALK2R206H-mediated BMP signaling is not well understood, and here we offer some insights into its molecular mechanism. We first demonstrated that among four BMP type I receptors, ALK2 is the only subtype able to mediate the activin A-induced BMP signaling upon the dissociation of FKBP12. We further showed that BMP4 does not cross-signal TGF-β pathway upon FKBP12 inhibition. In addition, although the roles of type II receptors in the ligand-independent BMP signaling activated by FOP-associated mutant ALK2 have been reported, their roles in activin A-induced BMP signaling remains unclear. We demonstrated in this study that the known type II BMP receptors contribute to activin A-induced BMP signaling through their kinase activity. Together, the current study provided important mechanistic insights at the molecular level into further understanding physiological and pathophysiological BMP signaling.

Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation

1999 ◽  
Vol 112 (20) ◽  
pp. 3519-3527 ◽  
Author(s):  
T. Ebisawa ◽  
K. Tada ◽  
I. Kitajima ◽  
K. Tojo ◽  
T.K. Sampath ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Osteoblast Differentiation ◽  
Transforming Growth Factor ◽  
C2c12 Cells ◽  
Nuclear Accumulation ◽  
Type I ◽  
Type Ii ◽  
Weakly Bound ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Bone morphogenetic protein (BMP)-6 is a member of the transforming growth factor (TGF)-(β) superfamily, and is most similar to BMP-5, osteogenic protein (OP)-1/BMP-7, and OP-2/BMP-8. In the present study, we characterized the endogenous BMP-6 signaling pathway during osteoblast differentiation. BMP-6 strongly induced alkaline phosphatase (ALP) activity in cells of osteoblast lineage, including C2C12 cells, MC3T3-E1 cells, and ROB-C26 cells. The profile of binding of BMP-6 to type I and type II receptors was similar to that of OP-1/BMP-7 in C2C12 cells and MC3T3-E1 cells; BMP-6 strongly bound to activin receptor-like kinase (ALK)-2 (also termed ActR-I), together with type II receptors, i.e. BMP type II receptor (BMPR-II) and activin type II receptor (ActR-II). In addition, BMP-6 weakly bound to BMPR-IA (ALK-3), to which BMP-2 also bound. In contrast, binding of BMP-6 to BMPR-IB (ALK-6), and less efficiently to ALK-2 and BMPR-IA, together with BMPR-II was detected in ROB-C26 cells. Intracellular signalling was further studied using C2C12 and MC3T3-E1 cells. Among the receptor-regulated Smads activated by BMP receptors, BMP-6 strongly induced phosphorylation and nuclear accumulation of Smad5, and less efficiently those of Smad1. However, Smad8 was constitutively phosphorylated, and no further phosphorylation or nuclear accumulation of Smad8 by BMP-6 was observed. These findings indicate that in the process of differentiation to osteoblasts, BMP-6 binds to ALK-2 as well as other type I receptors, and transduces signals mainly through Smad5 and possibly through Smad1.

scholarly journals Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin

Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 5195-5204 ◽  
Author(s):  
Yin Xia ◽  
Jodie L. Babitt ◽  
Yisrael Sidis ◽  
Raymond T. Chung ◽  
Herbert Y. Lin
Keyword(s):  
Iron Metabolism ◽  
Human Liver ◽  
Bmp Signaling ◽  
Type I ◽  
Type Ii ◽  
Hepcidin Expression ◽  
Bmp Receptors ◽  
Distinct Subset ◽  
Morphogenetic Protein

Abstract Hemojuvelin (HJV) is a coreceptor for bone morphogenetic protein (BMP) signaling that regulates hepcidin expression and iron metabolism. However, the precise combinations of BMP ligands and receptors used by HJV remain unknown. HJV has also been demonstrated to bind to neogenin, but it is not known whether this interaction has a role in regulating hepcidin expression. In the present study, we show that BMP-2, BMP-4, and BMP-6 are endogenous ligands for HJV in hepatoma-derived cell lines, and that all 3 of these ligands are expressed in human liver. We demonstrate in vitro that HJV selectively uses the BMP type II receptors ActRIIA and BMPRII, but not ActRIIB, and HJV enhances utilization of ActRIIA by BMP-2 and BMP-4. Interestingly, ActRIIA is the predominant BMP type II receptor expressed in human liver. While HJV can use all 3 BMP type I receptors (ALK2, ALK3, and ALK6) in vitro, only ALK2 and ALK3 are detected in human liver. Finally, we show that HJV-induced BMP signaling and hepcidin expression are not altered by neogenin overexpression or by inhibition of endogenous neogenin expression. Thus, HJV-mediated BMP signaling and hepcidin regulation occur via a distinct subset of BMP ligands and BMP receptors, independently of neogenin.

scholarly journals Bone Morphogenetic Protein Signaling Is Required for Maintenance of Differentiated Phenotype, Control of Proliferation, and Hypertrophy in Chondrocytes

1998 ◽  
Vol 140 (2) ◽  
pp. 409-418 ◽  
Author(s):  
Motomi Enomoto-Iwamoto ◽  
Masahiro Iwamoto ◽  
Yoshiki Mukudai ◽  
Yasuhiko Kawakami ◽  
Tsutomu Nohno ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alkaline Phosphatase ◽  
Bone Morphogenetic Protein ◽  
Bmp Signaling ◽  
Collagen Gene ◽  
Type Ii ◽  
Type X Collagen ◽  
Bmp Receptors ◽  
Collagen Gene Expression ◽  
Morphogenetic Protein

To examine the role of bone morphogenetic protein (BMP) signaling in chondrocytes during endochondral ossification, the dominant negative (DN) forms of BMP receptors were introduced into immature and mature chondrocytes isolated from lower and upper portions of chick embryo sternum, respectively. We found that control sternal chondrocyte populations expressed type IA, IB, and II BMP receptors as well as BMP-4 and -7. Expression of a DN-type II BMP receptor (termed DN-BMPR-II) in immature lower sternal (LS) chondrocytes led to a loss of differentiated functions; compared with control cells, the DN-BMPR- II–expressing LS chondrocytes proliferated more rapidly, acquired a fibroblastic morphology, showed little expression of type II collagen and aggrecan genes, and upregulated type I collagen gene expression. Expression of DN-BMPR-II in mature hypertrophic upper sternal (US) chondrocytes caused similar effects. In addition, the DN-BMPR-II–expressing US cells exhibited little alkaline phosphatase activity and type X collagen gene expression, while the control US cells produced both alkaline phosphatase and type X collagen. Both DN-BMPR-II–expressing US and LS chondrocytes failed to respond to treatment with BMP-2 . When we examined the effects of DN forms of types IA and IB BMP receptors, we found that DN-BMPR-IA had little effect, while DN-BMPR-IB had similar but weaker effects compared with those of DN-BMPR-II. We conclude that BMP signaling, particularly that mediated by the type II BMP receptor, is required for maintenance of the differentiated phenotype, control of cell proliferation, and expression of hypertrophic phenotype.

scholarly journals The finger 2 tip loop of Activin A is required for the formation of its non-signaling complex with ACVR1 and type II Bone Morphogenetic Protein receptors

2019 ◽  
Author(s):  
Senem Aykul ◽  
Richard A. Corpina ◽  
Erich J. Goebel ◽  
Camille J. Cunanan ◽  
Alexandra Dimitriou ◽  
...  
Keyword(s):  
Genetic Disorder ◽  
Severe Disease ◽  
Physiological Role ◽  
Activin A ◽  
Bmp Signaling ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Signaling Complex ◽  
Morphogenetic Protein ◽  
Protein Receptors

AbstractActivin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild type ACVR1. To explore the role of the NSC, we generated ‘agonist-only’ Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSC’s physiological role in corresponding knock-in mice.Impact StatementThe non-signaling complex formed by Activin A and ACVR1 is operant in vivo and is required to temper the degree of heterotopic ossification in the genetic disorder fibrodysplasia ossificans progressiva.

scholarly journals Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish

2020 ◽  
Author(s):  
Jelmer Hoeksma ◽  
Gerard C.M. van der Zon ◽  
Peter ten Dijke ◽  
Jeroen den Hertog
Keyword(s):  
Bone Morphogenetic Protein ◽  
Mammalian Cells ◽  
Kinase Activity ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Receptor Kinase ◽  
Developmental Defects ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
Constitutively Active

AbstractZebrafish models are well established tools for investigating underlying mechanisms of diseases. Here, we identified cercosporamide, a metabolite from the fungus Ascochyta aquiliqiae, as a potent bone morphogenetic protein (BMP) type I receptor kinase inhibitor through a zebrafish embryo phenotypic screen. The developmental defects in zebrafish, including lack of the ventral fin induced by cercosporamide was strikingly similar as the phenotypes caused by renowned small molecule BMP type I receptor kinase inhibitors and inactivating mutations in zebrafish BMP receptors. In mammalian cell-based assays, cercosporamide blocked BMP/SMAD-dependent transcriptional reporter activity and BMP-induced SMAD1/5-phosphorylation. Biochemical assays with a panel of purified recombinant kinases demonstrated that cercosporamide directly inhibited kinase activity of BMP type I receptors (also called activin receptor-like kinases (ALKs)). In mammalian cells, cercosporamide selectively inhibited constitutively active BMP type I receptor-induced SMAD1/5 phosphorylation. Importantly, cercosporamide rescued the developmental defects caused by constitutively active Alk2 in zebrafish embryos. Taken together, we believe cercosporamide may be the first of a new class of molecules with potential to be developed further for clinical use against diseases that are causally linked to overactivation of BMP receptor signaling, including Fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma.

scholarly journals Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Senem Aykul ◽  
Richard A Corpina ◽  
Erich J Goebel ◽  
Camille J Cunanan ◽  
Alexandra Dimitriou ◽  
...  
Keyword(s):  
Genetic Disorder ◽  
Severe Disease ◽  
Physiological Role ◽  
Activin A ◽  
Bmp Signaling ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Signaling Complex ◽  
Bmp Receptors

Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild-type ACVR1. To explore the role of the NSC, we generated ‘agonist-only’ Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins, we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSC’s physiological role in corresponding knock-in mice.

scholarly journals An anti-ACVR1 antibody exacerbates heterotopic ossification by fibro/adipogenic progenitors in fibrodysplasia ossificans progressiva mice

2021 ◽  
Author(s):  
John B Lees-Shepard ◽  
Sean J Stoessel ◽  
Julian Chandler ◽  
Keith Bouchard ◽  
Patricia Bento ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Mouse Models ◽  
Soft Tissues ◽  
Activin A ◽  
Bmp Signaling ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Morphogenetic Protein ◽  
Overexpressing Cell ◽  
Pathological Consequence

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive and catastrophic heterotopic ossification (HO) of skeletal muscle and associated soft tissues. FOP is caused by dominantly acting mutations in the bone morphogenetic protein (BMP) type I receptor, ACVR1 (also known as ALK2), the most prevalent of which is an arginine to histidine substitution [ACVR1(R206H)] in the glycine-serine rich intracellular domain of the receptor. A fundamental pathological consequence of FOP-causing ACVR1 receptor mutations is to enable activin A to initiate canonical BMP signaling in responsive progenitors, which drives skeletogenic commitment and HO. With the clear targets of activin A and ACVR1 identified, development of antibody therapeutics to prevent ligand-receptor interactions is an interventional approach currently being explored. Here, we developed a monoclonal blocking antibody (JAB0505) to the extracellular domain of ACVR1 and tested its ability to inhibit HO in established FOP mouse models. JAB0505 inhibited BMP-dependent gene expression in wild-type and ACVR1(R206H)-overexpressing cell lines. Strikingly, however, JAB0505 treatment markedly exacerbated injury-induced HO in two independent FOP mouse models in which ACVR1(R206H) was either broadly expressed, or more selectively expressed in fibro/adipogenic progenitors (FAPs). JAB0505 drove HO even under conditions of activin A inhibition, indicating that JAB0505 has receptor agonist activity. JAB0505-treated mice exhibited multiple, distinct foci of heterotopic lesions, suggesting an atypically broad anatomical domain of FAP recruitment to endochondral ossification. In addition, skeletogenic differentiation was both delayed and prolonged, and this was accompanied by dysregulation of FAP population growth. Collectively, alterations in the growth and differentiative properties of FAPs and FAP-derived skeletal cells are implicated in the aggravated HO phenotype. These data raise serious safety and efficacy concerns for the use of anti-ACVR1 antibodies to treat FOP patients.

scholarly journals Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Christopher Agnew ◽  
Pelin Ayaz ◽  
Risa Kashima ◽  
Hanna S. Loving ◽  
Prajakta Ghatpande ◽  
...  
Keyword(s):  
Md Simulations ◽  
Kinase Domain ◽  
Structural Basis ◽  
Type I ◽  
Type Ii ◽  
Exchange Mass Spectrometry ◽  
Receptor Complexes ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
Smad Proteins

AbstractUpon ligand binding, bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which then transmit signals to SMAD proteins. The link between receptor tetramerization and the mechanism of kinase activation, however, has not been elucidated. Here, using hydrogen deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, combined with analysis of SMAD signaling, we show that the kinase domain of the type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes. Formation of this dimer is essential for ligand-induced receptor signaling and is targeted by mutations in BMPR2 in patients with pulmonary arterial hypertension (PAH). We further show that the type I/type II kinase domain heterodimer serves as the scaffold for assembly of the active tetrameric receptor complexes to enable phosphorylation of the GS domain and activation of SMADs.

scholarly journals Connective Tissue Growth Factor Mediates Bone Morphogenetic Protein 2-Induced Increase in Hyaluronan Production in Luteinized Human Granulosa Cells

2021 ◽  
Author(s):  
Long Bai ◽  
Hsun-Ming Chang ◽  
Yi-Min Zhu ◽  
Peter CK Leung
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Bone Morphogenetic Protein ◽  
Molecular Mechanism ◽  
Granulosa Cells ◽  
Tissue Growth ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Human Granulosa Cells ◽  
Morphogenetic Protein

Abstract Background: Hyaluronan is the main component of the cumulus-oocyte complex (COC) matrix and it maintains the basic structure of the COC during ovulation. As a member of the transforming growth factor β (TGF-β) superfamily, bone morphogenetic protein 2 (BMP2) has been identified as a critical regulator of mammalian folliculogenesis and ovulation. However, whether BMP2 can regulate the production of hyaluronan in human granulosa cells has never been elucidated.Methods: In the present study, we investigated the effect of BMP2 on the production of hyaluronan and the underlying molecular mechanism using both immortalized (SVOG) and primary human granulosa-lutein (hGL) cells. The expression of three hyaluronan synthases (including HAS1, HAS2 and HAS3) were examined following cell incubation with BMP2 at different concentrations. The concentrations of the hyaluronan cell culture medium were determined by enzyme-linked immunosorbent assay (ELISA). The TGF-β type I receptor inhibitors (dorsomorphin and DMH-1) and small interfering RNAs targeting ALK2, ALK3, ALK6 and SMAD4 were used to investigate the involvement of TGF-β type I receptor and SMAD-dependent pathway.Results: Our results showed that BMP2 treatment significantly increased the production of hyaluronan by upregulating the expression of hyaluronan synthase 2 (HAS2). In addition, BMP2 upregulates the expression of connective tissue growth factor (CTGF), which subsequently mediates the BMP2-induced increases in HAS2 expression and hyaluronan production because overexpression of CTGF enhances, whereas knockdown of CTGF reverses, these effects. Notably, using kinase inhibitor- and siRNA-mediated knockdown approaches, we demonstrated that the inductive effect of BMP2 on the upregulation of CTGF is mediated by the ALK2/ALK3-mediated SMAD-dependent signaling pathway.Conclusions: Our findings provide new insight into the molecular mechanism by which BMP2 promotes the production of hyaluronan in human granulosa cells.

scholarly journals Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish

2020 ◽  
Vol 13 (9) ◽  
pp. dmm045971 ◽  
Author(s):  
Jelmer Hoeksma ◽  
Gerard C. M. van der Zon ◽  
Peter ten Dijke ◽  
Jeroen den Hertog
Keyword(s):  
Bone Morphogenetic Protein ◽  
Mammalian Cells ◽  
Kinase Activity ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Developmental Defects ◽  
Bone Morphogenetic Protein Receptor ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Constitutively Active

ABSTRACTZebrafish models are well-established tools for investigating the underlying mechanisms of diseases. Here, we identified cercosporamide, a metabolite from the fungus Ascochyta aquiliqiae, as a potent bone morphogenetic protein receptor (BMPR) type I kinase inhibitor through a zebrafish embryo phenotypic screen. The developmental defects in zebrafish, including lack of the ventral fin, induced by cercosporamide were strikingly similar to the phenotypes caused by renowned small-molecule BMPR type I kinase inhibitors and inactivating mutations in zebrafish BMPRs. In mammalian cell-based assays, cercosporamide blocked BMP/SMAD-dependent transcriptional reporter activity and BMP-induced SMAD1/5-phosphorylation. Biochemical assays with a panel of purified recombinant kinases demonstrated that cercosporamide directly inhibited kinase activity of type I BMPRs [also called activin receptor-like kinases (ALKs)]. In mammalian cells, cercosporamide selectively inhibited constitutively active BMPR type I-induced SMAD1/5 phosphorylation. Importantly, cercosporamide rescued the developmental defects caused by constitutively active Alk2 in zebrafish embryos. We believe that cercosporamide could be the first of a new class of molecules with potential to be developed further for clinical use against diseases that are causally linked to overactivation of BMPR signaling, including fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma.This article has an associated First Person interview with the first author of the paper.

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