scholarly journals Netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ahmad Abdullah ◽  
Carl Herdenberg ◽  
Håkan Hedman
Keyword(s):  
Bone Morphogenetic Protein ◽  
Molecular Mechanisms ◽  
Bmp Signaling ◽  
Cellular Systems ◽  
Axonal Guidance ◽  
Inhibitory Interaction ◽  
Inhibitory Function ◽  
Morphogenetic Protein ◽  
Cell Metastasis ◽  
Leucine Rich Repeats

AbstractNetrin-1 is a secreted protein that is well known for its involvement in axonal guidance during embryonic development and as an enhancer of cancer cell metastasis. Despite extensive efforts, the molecular mechanisms behind many of the physiological functions of netrin-1 have remained elusive. Here, we show that netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling in various cellular systems, including a mutually inhibitory interaction with the BMP-promoting function of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins. The BMP inhibitory function of netrin-1 in mouse embryonic fibroblasts was dependent on the netrin receptor neogenin, with the expression level regulated by both netrin-1 and LRIG proteins. Our results reveal a previously unrecognized function of netrin-1 that may help to explain several of the developmental, physiological, and cancer-promoting functions of netrins at the signal transduction level.

scholarly journals Bone Morphogenetic Protein Signaling Restricts Proximodistal Extension of the Ventral Fin Fold

2020 ◽  
Vol 8 ◽  
Author(s):  
Jun Ka ◽  
Jun-Dae Kim ◽  
Boryeong Pak ◽  
Orjin Han ◽  
Woosoung Choi ◽  
...  
Keyword(s):  
Cell Division ◽  
Bone Morphogenetic Protein ◽  
Molecular Mechanisms ◽  
Bmp Signaling ◽  
Protein Signaling ◽  
Morphogenetic Protein ◽  
Distal Migration ◽  
Cellular Behaviors ◽  
And Shifts ◽  
Migration Of Cells

Unpaired fins, which are the most ancient form of locomotory appendages in chordates, had emerged at least 500 million years ago. While it has been suggested that unpaired fins and paired fins share structural similarities, cellular and molecular mechanisms that regulate the outgrowth of the former have not been fully elucidated yet. Using the ventral fin fold in zebrafish as a model, here, we investigate how the outgrowth of the unpaired fin is modulated. We show that Bone Morphogenetic Protein (BMP) signaling restricts extension of the ventral fin fold along the proximodistal axis by modulating diverse aspects of cellular behaviors. We find that lack of BMP signaling, either caused by genetic or chemical manipulation, prolongs the proliferative capacity of epithelial cells and substantially increases the number of cells within the ventral fin fold. In addition, inhibition of BMP signaling attenuates the innate propensity of cell division along the anteroposterior axis and shifts the orientation of cell division toward the proximodistal axis. Moreover, abrogating BMP signaling appears to induce excessive distal migration of cells within the ventral fin fold, and therefore precipitates extension along the proximodistal axis. Taken together, our data suggest that BMP signaling restricts the outgrowth of the ventral fin fold during zebrafish development.

Abstract 130: Arginine Methylation of Smad6 Defines Bone-morphogenetic-protein (BMP) Signaling Duration and Intensity

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
JIAN WU ◽  
Olan Jackson-Weaver ◽  
Tingwei Zhang ◽  
Yongchao Gou ◽  
Jian Xu
Keyword(s):  
Complex Formation ◽  
Cell Surface ◽  
Bone Morphogenetic Protein ◽  
Arginine Methylation ◽  
Bmp Signaling ◽  
Type I ◽  
Surface Level ◽  
Inhibitory Function ◽  
Morphogenetic Protein ◽  
Cell Surface Level

Bone-morphogenetic-protein (BMP)/Smads signaling pathway plays crucial role during heart development and vessel angiogenesis. BMP signaling is induced by the binding of BMP ligands (eg. BMP4) to their receptors, which recruit and phosphorylate receptor-Smads (R-Smads, eg. Smad1, Smad5) that form nuclear-transporting complexes with Smad4 for transcriptional regulation. Smad6 is an inhibitory Smad expresses predominantly in atria-ventricular cushion and outflow tract of the developing mouse heart, and expands to valves and great vessels. At the cell surface level, Smad6 binds to BMP type I receptor to block R-Smads recruitment to the receptor. At cytosolic level, Smad6 block Smad1/Smad4 complex formation. In the nucleus, Smad6 represses transcription. How these three levels of regulation are coordinated to inhibit BMP signaling is not known. We previously showed that BMP ligand induces an acute Smad6 methylation at arginine 74 (R74) at the cell surface level by a methyltransferase PRMT1, and methyl-Smad6 dissociates from receptor to allow receptor-induced Smad1/5 phosphorylation and activation. We further identified a delayed methylation on arginine 81 (R81) of Smad6 in the cytosol by PRMT1. We found that R81 methylation is required for BMP signaling-induced recruitment of Smad6 to phosphor-Smad1; it is also required for Smad6 to disrupt phosphor-Smad1/Smad4 complex formation and the following nuclear transportation, as well as for Smad6 to suppress Smad1 targeting gene transactivation. Previous findings indicate that Smad6 binds to type I receptor and Smad1 through its C-terminal region. We examined how arginine methylation in the N-terminal region, regulates the binding properties of C-terminal Smad6. We found that N-terminal Smad6 stabilizes the interaction between C-terminal Smad6 and Smad1 and enhances Smad6 inhibitory function. Disruption of R81 methylation results in loss of inhibitory function because of an increase in binding between N-term and C-term Smad6 that results in a "closed" conformation. In summary, R81 methylation controls Smad6 activity and R81 methylation of Smad6 defines the duration and intensity of BMP-induced Smad1/5 signaling.

scholarly journals Paracrine Bone Morphogenetic Protein Signaling in Iron Homeostasis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-26-SCI-26
Author(s):  
Jodie L. Babitt
Keyword(s):  
Iron Deficiency ◽  
Bone Morphogenetic Protein ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Bmp Signaling ◽  
Free Oxygen Radicals ◽  
Iron Loading ◽  
Iron Availability ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Iron is an essential nutrient that is required not only for hemoglobin production in red blood cells, but also as a co-factor of many other proteins that perform fundamental cellular processes. However, excess iron can generate free oxygen radicals that can be toxic. Cells and organisms have therefore evolved mechanisms to tightly control iron levels. Systemic iron homeostasis is governed by the iron hormone hepcidin that binds and degrades the iron exporter ferroportin to limit iron absorption from dietary sources and iron release from iron-recycling macrophages and hepatocyte stores. The key source of hepcidin that controls systemic iron homeostasis is the liver. Hepcidin production by the liver is coordinated by several signals that communicate the body's iron needs. Increases in serum and tissue iron induce hepcidin production, whereas iron deficiency suppresses hepcidin production, as feedback mechanisms to maintain steady state iron levels. Inflammation induces hepcidin to limit iron availability to infectious organisms that also require iron to grow and proliferate. Increases in erythropoietic drive suppress hepcidin production to increase iron availability for red blood cell production. The bone morphogenetic protein (BMP) signaling pathway is the central signal transduction pathway that controls hepcidin production in the liver. Activation of BMP signaling by iron loading or suppression of BMP signaling by iron deficiency or erythropoietic drive are key mechanisms by which these signals control hepcidin transcription. Iron loading increases production of BMP6 and BMP2 ligands by liver endothelial cells. Endothelial-derived BMP6 and BMP2 have paracrine actions on BMP receptors and the co-receptor hemojuvelin on hepatocytes to phosphorylate SMAD transcription factors, which translocate to the nucleus to regulate hepcidin transcription. Erythropoietic drive increases the production of erythroferrone by erythrocyte precursors. Erythroferrone is secreted into the circulation where it binds BMP ligands to prevent their interaction with cell surface receptors, thereby inhibiting hepcidin transcription. This talk will focus on recent insights into the molecular mechanisms by whch paracrine BMP signaling in the liver coordinates hepcidin production to regulate systemic iron homeostasis. Disclosures Babitt: Ferrumax Pharmaceuticals, Inc: Equity Ownership, Patents & Royalties; Keryx BIopharmaceuticals, Inc (now part of Akebia Therapeutics): Consultancy; Disc Medicine: Consultancy.

scholarly journals Bone morphogenetic protein 2 inhibits growth differentiation factor 8-induced cell signaling via upregulation of gremlin2 expression in human granulosa-lutein cells

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiaoyan Luo ◽  
Hsun-Ming Chang ◽  
Yuyin Yi ◽  
Yingpu Sun ◽  
Peter C. K. Leung
Keyword(s):  
Bone Morphogenetic Protein ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Dependent Manner ◽  
Small Interfering Rnas ◽  
Differentiation Factor ◽  
Morphogenetic Protein

Abstract Background Bone morphogenetic protein 2 (BMP2), growth differentiation factor 8 (GDF8) and their functional receptors are expressed in human ovarian follicles, and these two intrafollicular factors play essential roles in regulating follicle development and luteal function. As BMP antagonists, gremlin1 (GREM1) and gremlin2 (GREM2) suppress BMP signaling through blockage of ligand-receptor binding. However, whether BMP2 regulates the expression of GREM1 and GREM2 in follicular development remains to be determined. Methods In the present study, we investigated the effect of BMP2 on the expression of GREM1 and GREM2 and the underlying mechanisms in human granulosa-lutein (hGL) cells. An established immortalized human granulosa cell line (SVOG) and primary hGL cells were used as study models. The expression of GREM1 and GREM2 were examined following cell incubation with BMP2 at different concentrations and time courses. The TGF-β type I inhibitors (dorsomorphin, DMH-1 and SB431542) and small interfering RNAs targeting ALK2, ALK3, SMAD2/3, SMAD1/5/8 and SMAD4 were used to investigate the involvement of the SMAD-dependent pathway. Results Our results showed that BMP2 significantly increased the expression of GREM2 (but not GREM1) in a dose- and time-dependent manner. Using a dual inhibition approach combining kinase inhibitors and siRNA-mediated knockdown, we found that the BMP2-induced upregulation of GREM2 expression was mediated by the ALK2/3-SMAD1/5-SMAD4 signaling pathway. Moreover, we demonstrated that BMP2 pretreatment significantly attenuated the GDF8-induced phosphorylation of SMAD2 and SMAD3, and this suppressive effect was reversed by knocking down GREM2 expression. Conclusions Our findings provide new insight into the molecular mechanisms by which BMP2 modulates the cellular activity induced by GDF8 through the upregulated expression of their antagonist (GREM2).

Extracellular regulation of BMP signaling: welcome to the matrix

2017 ◽  
Vol 45 (1) ◽  
pp. 173-181 ◽  
Author(s):  
Georg Sedlmeier ◽  
Jonathan P. Sleeman
Keyword(s):  
Extracellular Matrix ◽  
Physical Properties ◽  
Bone Morphogenetic Protein ◽  
Bmp Signaling ◽  
Intracellular Level ◽  
Morphogenetic Protein ◽  
The Matrix ◽  
Mechanical Barrier

Given its importance in development and homeostasis, bone morphogenetic protein (BMP) signaling is tightly regulated at the extra- and intracellular level. The extracellular matrix (ECM) was initially thought to act as a passive mechanical barrier that sequesters BMPs. However, a new understanding about how the ECM plays an instructive role in regulating BMP signaling is emerging. In this mini-review, we discuss various ways in which the biochemical and physical properties of the ECM regulate BMP signaling.

Abstract 17763: Inhibition of Bone Morphogenetic Protein Signaling Reduces Endothelial-Mesenchymal Transition and Vascular Smooth Muscle Cell Calcification Associated with Matrix Gla Protein Deficiency

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Megan F Burke ◽  
Caitlin O’Rourke ◽  
Trejeeve Martyn ◽  
Hannah R Shakartzi ◽  
Timothy E Thayer ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Bone Morphogenetic Protein ◽  
Vascular Calcification ◽  
Bmp Signaling ◽  
Matrix Gla Protein ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Morphogenetic Protein ◽  
Endothelial Mesenchymal Transition

Background: Matrix Gla protein (MGP) is an extracellular matrix protein that inhibits bone morphogenetic protein (BMP) signaling in vitro. MGP deficiency induces vascular calcification associated with osteogenic transdifferentiation of endothelial cells (via endothelial-mesenchymal transition, EndMT) and vascular smooth muscle cells (VSMCs). We previously reported that treatment with two pharmacologic inhibitors of BMP signaling reduced aortic calcification in MGP-/- mice. We hypothesized that BMP signaling is essential for EndMT and VSMC osteogenic transdifferentiation induced by MGP deficiency. Methods and Results: Aortic levels of mRNAs encoding markers of osteogenesis (Runx2 and osteopontin) and EndMT (nanog, Sox2, and Oct3/4) were greater in MGP-/- than in wild-type mice (P<0.01 for all). Aortic expression of markers of VSMC differentiation (α-smooth muscle actin, transgelin, and calponin) was less in MGP-/- than in wild-type mice (P<0.001 for all). Treatment of MGP-/- mice with the BMP signaling inhibitor, LDN-193189, reduced expression of both osteogenic and EndMT markers (P<0.05 for all) but did not prevent VSMC de-differentiation. Depletion of MGP in cultured wild-type VSMCs with siRNA specific for MGP (siMGP) was associated with a 30-40% reduction in levels of mRNAs encoding markers of VSMC differentiation (P<0.05 for all), an effect that was not prevented by LDN-193189. Incubation in phosphate-containing media induced greater calcification in siMGP-treated VSMCs than in cells treated with control siRNA (P<0.0001). Treatment with LDN-193189 reduced calcification in siMGP-treated VSMCs (50%, P=0.0003). Conversely, infection of MGP-/- VSMCs with adenovirus specifying MGP increased expression of markers of VSMC differentiation by 60-80% (P<0.01 for all) and decreased calcification by 74% (P=0.03). Conclusions: Inhibition of BMP signaling suppresses osteogenic and EndMT gene programs in MGP-/- mice and reduces calcification of siMGP-treated VSMCs. However, MGP deficiency induces VSMC de-differentiation via a BMP-independent mechanism. These findings suggest that the processes underlying vascular calcification in MGP deficiency are mediated by both BMP signaling-dependent and -independent mechanisms.

Expression of bone morphogenetic protein receptors in bovine oviductal epithelial cells: Evidence of autocrine BMP signaling

2017 ◽  
Vol 185 ◽  
pp. 89-96 ◽  
Author(s):  
Pablo Alberto Valdecantos ◽  
Rocío del Carmen Bravo Miana ◽  
Elina Vanesa García ◽  
Daniela Celeste García ◽  
Mariela Roldán-Olarte ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Bone Morphogenetic Protein ◽  
Bmp Signaling ◽  
Morphogenetic Protein ◽  
Protein Receptors ◽  
Bone Morphogenetic Protein Receptors

scholarly journals At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1371
Author(s):  
Meghan M. Cirulis ◽  
Mark W. Dodson ◽  
Lynn M. Brown ◽  
Samuel M. Brown ◽  
Tim Lahm ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Bone Morphogenetic Protein ◽  
Pulmonary Arteries ◽  
Bmp Signaling ◽  
Signaling Cascades ◽  
Estrogen Signaling ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Pulmonary Arterial

Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH.

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