scholarly journals The Bone Morphogenetic Protein Type Ib Receptor Is a Major Mediator of Glial Differentiation and Cell Survival in Adult Hippocampal Progenitor Cell Culture

2004 ◽  
Vol 15 (8) ◽  
pp. 3863-3875 ◽  
Author(s):  
A. Brederlau ◽  
R. Faigle ◽  
M. Elmi ◽  
A. Zarebski ◽  
S. Sjöberg ◽  
...  
Keyword(s):  
Cell Survival ◽  
Bone Morphogenetic Protein ◽  
Cell Fate ◽  
Bone Morphogenetic Proteins ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Type I ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Mediate Cell

Bone morphogenetic proteins (BMPs) act as growth regulators and inducers of differentiation. They transduce their signal via three different type I receptors, termed activin receptor-like kinase 2 (Alk2), Alk3, or bone morphogenetic protein receptor Ia (BMPRIa) and Alk6 or BMPRIb. Little is known about functional differences between the three type I receptors. Here, we have investigated consequences of constitutively active (ca) and dominant negative (dn) type I receptor overexpression in adult-derived hippocampal progenitor cells (AHPs). The dn receptors have a nonfunctional intracellular but functional extracellular domain. They thus trap BMPs that are endogenously produced by AHPs. We found that effects obtained by overexpression of dnAlk2 and dnAlk6 were similar, suggesting similar ligand binding patterns for these receptors. Thus, cell survival was decreased, glial fibrillary acidic protein (GFAP) expression was reduced, whereas the number of oligodendrocytes increased. No effect on neuronal differentiation was seen. Whereas the expression of Alk2 and Alk3 mRNA remained unchanged, the Alk6 mRNA was induced after impaired BMP signaling. After dnAlk3 overexpression, cell survival and astroglial differentiation increased in parallel to augmented Alk6 receptor signaling. We conclude that endogenous BMPs mediate cell survival, astroglial differentiation and the suppression of oligodendrocytic cell fate mainly via the Alk6 receptor in AHP culture.

scholarly journals Bone morphogenetic protein receptor 2 inhibition destabilizes microtubules promoting the activation of lysosomes and cell death of lung cancer cells

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Arindam Mondal ◽  
Rachel NeMoyer ◽  
Mehul Vora ◽  
Logan Napoli ◽  
Zoya Syed ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cell Survival ◽  
Cancer Cells ◽  
Bone Morphogenetic Protein ◽  
Neurological Diseases ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein Receptor ◽  
Protein Receptor ◽  
Morphogenetic Protein

Abstract Background Recent studies have shown that bone morphogenetic protein receptor 2 (BMPR2) regulates cell survival signaling events in cancer cells independent of the BMP type 1 receptor (BMPR1) or the Smad-1/5 transcription factor. Mutations in BMPR2 trafficking proteins leads to overactive BMP signaling, which leads to neurological diseases caused by BMPR2 stabilization of the microtubules. It is not known whether BMPR2 regulates the microtubules in cancer cells and what effect this has on cell survival. It is also not known whether alterations in BMPR2 trafficking effects activity and response to BMPR2 inhibitors. Methods We utilized BMPR2 siRNA and the BMP receptor inhibitors JL5 and Ym155, which decrease BMPR2 signaling and cause its mislocalization to the cytoplasm. Using the JL5 resistant MDA-MD-468 cell line and sensitive lung cancer cell lines, we examined the effects of BMPR2 inhibition on BMPR2 mislocalization to the cytoplasm, microtubule destabilization, lysosome activation and cell survival. Results We show that the inhibition of BMPR2 destabilizes the microtubules. Destabilization of the microtubules leads to the activation of the lysosomes. Activated lysosomes further decreases BMPR2 signaling by causing it to mislocalizated to the cytoplasm and/or lysosome for degradation. Inhibition of the lysosomes with chloroquine attenuates BMPR2 trafficking to the lysosome and cell death induced by BMPR2 inhibitors. Furthermore, in MDA-MD-468 cells that are resistant to JL5 induced cell death, BMPR2 was predominately located in the cytoplasm. BMPR2 failed to localize to the cytoplasm and/or lysosome following treatment with JL5 and did not destabilize the microtubules or activate the lysosomes. Conclusions These studies reveal that the inhibition of BMPR2 destabilizes the microtubules promoting cell death of cancer cells that involves the activation of the lysosomes. Resistance to small molecules targeting BMPR2 may occur if the BMPR2 is localized predominantly to the cytoplasm and/or fails to localize to the lysosome for degradation.

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.

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.

scholarly journals Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

Blood ◽  
2011 ◽  
Vol 117 (18) ◽  
pp. 4915-4923 ◽  
Author(s):  
Andrea U. Steinbicker ◽  
Chetana Sachidanandan ◽  
Ashley J. Vonner ◽  
Rushdia Z. Yusuf ◽  
Donna Y. Deng ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Iron Homeostasis ◽  
Iron Bioavailability ◽  
Bmp Signaling ◽  
Neoplastic Disease ◽  
Type I ◽  
Hepcidin Expression ◽  
Hepatic Expression ◽  
Morphogenetic Protein ◽  
Anemia Of Inflammation

Abstract Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6–induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.

scholarly journals Statin-induced Ras Activation Integrates the Phosphatidylinositol 3-Kinase Signal to Akt and MAPK for Bone Morphogenetic Protein-2 Expression in Osteoblast Differentiation

2006 ◽  
Vol 282 (7) ◽  
pp. 4983-4993 ◽  
Author(s):  
Nandini Ghosh-Choudhury ◽  
Chandi Charan Mandal ◽  
Goutam Ghosh Choudhury
Keyword(s):  
Bone Morphogenetic Protein ◽  
Osteoblast Differentiation ◽  
Dominant Negative ◽  
Bone Morphogenetic Protein 2 ◽  
Regulatory Subunit ◽  
Type I ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Morphogenetic Protein ◽  
Phosphatidylinositol 3

Lovastatin promotes osteoblast differentiation by increasing bone morphogenetic protein-2 (BMP-2) expression. We demonstrate that lovastatin stimulates tyrosine phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to an increase in its kinase activity in osteoblast cells. Inhibition of PI3K ameliorated expression of the osteogenic markers alkaline phosphatase, type I collagen, osteopontin, and BMP-2. Expression of dominant-negative PI3K and PTEN, an inhibitor of PI3K signaling, significantly attenuated lovastatin-induced transcription of BMP-2. Akt kinase was also activated in a PI3K-dependent manner. However, our data suggest involvement of an additional signaling pathway. Lovastatin-induced Erk1/2 activity contributed to BMP-2 transcription. Inhibition of PI3K abrogated Erk1/2 activity in response to lovastatin, indicating the presence of a signal relay between them. We provide, as a mechanism of this cross-talk, the first evidence that lovastatin stimulates rapid activation of Ras, which associates with and activates PI3K in the plasma membrane, which in turn regulates Akt and Erk1/2 to induce BMP-2 expression for osteoblast differentiation.

Hemojuvelin Acts as a Bone Morphogenetic Protein Co-Receptor To Regulate Hepcidin Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 511-511 ◽  
Author(s):  
Franklin W. Huang ◽  
Jodie L. Babitt ◽  
Diedra M. Wrighting ◽  
Tarek A. Samad ◽  
Yin Xia ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Bone Morphogenetic Protein ◽  
Signal Transduction Pathway ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Transduction Pathway ◽  
Reporter Construct ◽  
Hepcidin Expression ◽  
Morphogenetic Protein ◽  
Juvenile Hemochromatosis

Abstract Juvenile hemochromatosis is a severe iron overload disorder resulting from mutations in the hemojuvelin (HJV) gene. To understand its pathogenesis, we developed Hjv−/− mice. Similar to human patients, Hjv−/− animals accumulate excess iron in the liver, pancreas and heart early in life. Tissue macrophages are iron-depleted. Hjv−/− mice express very low levels of hepcidin mRNA and, likely as a consequence, have elevated expression of the iron transporter ferroportin in enterocytes and macrophages. These results suggested that Hjv plays a role in regulating hepcidin expression. Two known Hjv homologs, Rgma and Rgmb, have previously been shown to act as bone morphogenetic protein (BMP) co-receptors. We hypothesized that Hjv regulates hepcidin expression through a BMP signal transduction pathway. We found that Hjv binds radiolabeled BMP, supporting the contention that it is a BMP co-receptor. Transfection of HepG2 cells with Hjv cDNA activated a BMP-responsive reporter construct and augmented its response to exogenous BMP. Both an anti-BMP neutralizing antibody and the natural BMP antagonist Noggin blocked this response, as did co-expressed dominant negative BMP receptor proteins. When cells were transfected with a construct carrying an Hjv mutation known to cause human disease, BMP reporter activation was significantly reduced in the presence and absence of exogenous BMP. Treatment with BMP stimulated hepcidin production in hepatoma cells and activated a reporter construct containing a fragment of the hepcidin promoter. To extend these results, we studied tissues from Hjv−/− mice. BMP signals are transduced through phosphorylation of Smad proteins. We found that Smads 1, 5 and 8 were hypophosphorylated in Hjv−/− liver, consistent with impaired BMP signaling. BMP treatment of wild type and Hjv−/− primary hepatocytes induced hepcidin expression, but induction was blunted in cells from Hjv−/− animals. Taken together, these data suggest that the normal hepatic function of Hjv is to serve as a BMP co-receptor, modulating a signal transduction pathway that culminates in hepcidin expression. [Note - Jodie L. Babitt is the first author of this abstract, but it will be presented by Franklin W. Huang, the second author]

scholarly journals Association of distinct type 1 bone morphogenetic protein receptors with different molecular pathways and survival outcomes in neuroblastoma

2020 ◽  
Vol 4 (1) ◽  
Author(s):  
Amnah M. Alshangiti ◽  
Sean L. Wyatt ◽  
Erin McCarthy ◽  
Louise M. Collins ◽  
Shane V. Hegarty ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Bone Morphogenetic Proteins ◽  
Sympathetic Neurons ◽  
Distinct Type ◽  
Dominant Negative ◽  
Survival Outcomes ◽  
Mycn Amplification ◽  
Morphogenetic Protein ◽  
Stage 4 ◽  
Cultured Sympathetic Neurons

Abstract Neuroblastoma (NB) is a paediatric cancer that arises in the sympathetic nervous system. Patients with stage 4 tumours have poor outcomes and 20% of high-risk cases have MYCN amplification. The bone morphogenetic proteins (BMPs) play roles in sympathetic neuritogenesis, by signalling through bone morphogenetic protein receptor (BMPR)2 and either BMPR1A or BMPR1B. Alterations in BMPR2 expression have been reported in NB; it is unknown if the expression of BMPR1A or BMPR1B is altered. We report lower BMPR2 and BMPR1B, and higher BMPR1A, expression in stage 4 and in MYCN-amplified NB. Kaplan–Meier plots showed that high BMPR2 or BMPR1B expression was linked to better survival, while high BMPR1A was linked to worse survival. Gene ontology enrichment and pathway analyses revealed that BMPR2 and BMPR1B co-expressed genes were enriched in those associated with NB differentiation. BMPR1A co-expressed genes were enriched in those associated with cell proliferation. Moreover, the correlation between BMPR2 and BMPR1A was strengthened, while the correlation between BMPR2 and BMPR1B was lost, in MYCN-amplified NB. This suggested that differentiation should decrease BMPR1A and increase BMPR1B expression. In agreement, nerve growth factor treatment of cultured sympathetic neurons decreased Bmpr1a expression and increased Bmpr1b expression. Overexpression of dominant negative BMPR1B, treatment with a BMPR1B inhibitor and treatment with GDF5, which signals via BMPR1B, showed that BMPR1B signalling is required for optimal neuritogenesis in NB cells, suggesting that loss of BMPR1B may alter neuritogenesis. The present study shows that expression of distinct BMPRs is associated with different survival outcomes in NB.

BMP signaling during bone pattern determination in the developing limb

Development ◽  
1996 ◽  
Vol 122 (11) ◽  
pp. 3557-3566 ◽  
Author(s):  
Y. Kawakami ◽  
T. Ishikawa ◽  
M. Shimabara ◽  
N. Tanda ◽  
M. Enomoto-Iwamoto ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Kinase Domain ◽  
Distal Region ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Limb Bud ◽  
Type I ◽  
Posterior Limb ◽  
Receptor Complexes ◽  
Limb Mesenchyme

To examine the role of BMP signaling during limb pattern formation, we isolated chicken cDNAs encoding type I (BRK-1 and BRK-2) and type II (BRK-3) receptors for bone morphogenetic proteins. BRK-2 and BRK-3, which constitute dual-affinity signaling receptor complexes for BMPs, are co-expressed in condensing precartilaginous cells, while BRK-1 is weakly expressed in the limb mesenchyme. BRK-3 is also expressed in the apical ectodermal ridge and interdigital limb mesenchyme. BRK-2 is intensely expressed in the posterior-distal region of the limb bud. During digit duplication by implanting Sonic hedgehog-producing cells, BRK-2 expression is induced anteriorly in the new digit forming region as observed for BMP-2 and BMP-7 expression in the limb bud. Dominant-negative effects on BMP signaling were obtained by over-expressing kinase domain-deficient forms of the receptors. Chondrogenesis of limb mesenchymal cells is markedly inhibited by dominant-negative BRK-2 and BRK-3, but not by BRK-1. Although the bone pattern was not disturbed by expressing individual dominant-negative BRK independently, preferential distal and posterior limb truncations resulted from co-expressing the dominant-negative forms of BRK-2 and BRK-3 in the whole limb bud, thus providing evidence that BMPs are essential morphogenetic signals for limb bone patterning.

XBMPRII, a novel Xenopus type II receptor mediating BMP signaling in embryonic tissues

Development ◽  
1998 ◽  
Vol 125 (3) ◽  
pp. 431-442 ◽  
Author(s):  
A. Frisch ◽  
C.V. Wright
Keyword(s):  
Cell Fate ◽  
Organizer Region ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Mesoderm Induction ◽  
Type I ◽  
Type Ii ◽  
Common Component ◽  
Activin Signaling

Bone Morphogenetic Proteins (BMPs) are potent regulators of embryonic cell fate that are presumed to initiate signal transduction in recipient cells through multimeric, transmembrane, serine/threonine kinase complexes made up of type I and type II receptors. BMPRII was identified previously in mammals as the only type II receptor that binds BMPs, but not activin or TGFbeta, in vitro. We report the cloning and functional analysis in vivo of its Xenopus homolog, XBMPRII. XBMPRII is expressed maternally and zygotically in an initially unrestricted manner. Strikingly, XBMPRII transcripts then become restricted to the mesodermal precursors during gastrulation. Expression is lower in the dorsal organizer region, potentially providing a mechanism to suppress the actions of BMP4 on dorsally fated tissues. Similar to the results seen for a truncated type I BMP receptor (tBR), a dominant-negative form of XBMPRII (tBRII) can dorsalize ventral mesoderm, induce extensive secondary body axes, block mesoderm induction by BMP4 and directly neuralize ectoderm, strongly suggesting that XBMPRII mediates BMP signals in vivo. However, although both tBRII and tBR can induce partial secondary axes, marker analysis shows that tBRII-induced axes are more anteriorly extended. Additionally, coinjection of tBRII and tBR synergistically increases the incidence of secondary axis formation. A truncated activin type II receptor (deltaXAR1) is known to block both activin and BMP signaling in vivo. Here we show that such crossreactivity does not occur for tBRII, in that it does not affect activin signaling. Furthermore, our studies indicate that the full-length activin type II receptor (XAR1) overcomes a block in BMP4 signaling imposed by tBRII, implicating XAR1 as a common component of BMP and activin signaling pathways in vivo. These data implicate XBMPRII as a type II receptor with high selectivity for BMP signaling, and therefore as a critical mediator of the effects of BMPs as mesodermal patterning agents and suppressors of neural fate during embryogenesis.

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.

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