scholarly journals Estradiol Upregulates the Expression of the TGF-β Receptors ALK5 and BMPR2 during the Gonadal Development of Schizothorax prenanti

Animals ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 1365
Author(s):  
Taiming Yan ◽  
Songpei Zhang ◽  
Yueping Cai ◽  
Zhijun Ma ◽  
Jiayang He ◽  
...  
Keyword(s):  
Expression Patterns ◽  
Gonadal Development ◽  
Vital Role ◽  
Type I ◽  
Amino Acid Residues ◽  
Schizothorax Prenanti ◽  
Cdna Sequences ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Receptor Like Kinase

TGF-β receptors play important roles in mediating TGF-β signals during gonadal development. To identify the functions of TGF-β receptors, including the type I receptor (activin receptor-like kinase 5, ALK5) and type II receptor (bone morphogenetic protein receptor 2, BMPR2), during the gonadal development of S. prenanti, the full-length cDNA sequences of ALK5 and BMPR2 were isolated and characterized. Their expression patterns in developing gonads and in the gonads of exogenous estradiol (E2) -fed fish were analyzed. The cDNAs of ALK5 and BMPR2 were 1925 bp and 3704 bp in length and encoded 501 and 1070 amino acid residues, respectively. ALK5 and BMPR2 were mostly expressed in gonads, particularly in cortical alveoli stage ovaries and mid-spermatogenic stage testes; however, the overall level of BMPR2 mRNA was higher than that of ALK5 during gonadal development. Furthermore, immunohistochemical signals of ALK5 and BMPR2 were mostly detected at chromatin nucleolar oocytes and perinuclear oocytes in ovaries and at spermatocytes and spermatogonia in testes. Exogenous E2 induces the gonadal expression of ALK5 and BMPR2, and BMPR2 is more responsive to E2 than ALK5. These results suggest that ALK5 and BMPR2 might play a potentially vital role in both folliculogenesis and spermatogenesis in S. prenanti.

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 Future treatments for hereditary hemorrhagic telangiectasia

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Florian Robert ◽  
Agnès Desroches-Castan ◽  
Sabine Bailly ◽  
Sophie Dupuis-Girod ◽  
Jean-Jacques Feige
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Vascular Endothelial ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Receptor Like Kinase ◽  
Recent Developments ◽  
Frequent Mutations ◽  
Transcriptional Complex ◽  
Angiopoietin 2 ◽  
Endothelial Growth Factor

AbstractHereditary Hemorrhagic Telangiectasia (HHT), also known as Rendu-Osler syndrome, is a genetic vascular disorder affecting 1 in 5000–8000 individuals worldwide. This rare disease is characterized by various vascular defects including epistaxis, blood vessel dilations (telangiectasia) and arteriovenous malformations (AVM) in several organs. About 90% of the cases are associated with heterozygous mutations of ACVRL1 or ENG genes, that respectively encode a bone morphogenetic protein receptor (activin receptor-like kinase 1, ALK1) and a co-receptor named endoglin. Less frequent mutations found in the remaining 10% of patients also affect the gene SMAD4 which is part of the transcriptional complex directly activated by this pathway. Presently, the therapeutic treatments for HHT are intended to reduce the symptoms of the disease. However, recent progress has been made using drugs that target VEGF (vascular endothelial growth factor) and the angiogenic pathway with the use of bevacizumab (anti-VEGF antibody). Furthermore, several exciting high-throughput screenings and preclinical studies have identified new molecular targets directly related to the signaling pathways affected in the disease. These include FKBP12, PI3-kinase and angiopoietin-2. This review aims at reporting these recent developments that should soon allow a better care of HHT patients.

A Caenorhabditis elegans type I TGF beta receptor can function in the absence of type II kinase to promote larval development

Development ◽  
2000 ◽  
Vol 127 (15) ◽  
pp. 3337-3347 ◽  
Author(s):  
C.V. Gunther ◽  
L.L. Georgi ◽  
D.L. Riddle
Keyword(s):  
Caenorhabditis Elegans ◽  
Fluorescent Protein ◽  
Type I ◽  
Receptor Complex ◽  
Type Ii ◽  
Precise Control ◽  
Dauer Larva ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Green Fluorescent

The daf-4 gene encodes a type II bone morphogenetic protein receptor in Caenorhabditis elegans that regulates dauer larva formation, body size and male tail patterning. The putative type I receptor partner for DAF-4 in regulating dauer larva formation is DAF-1. Genetic tests of the mechanism of activation of these receptors show that DAF-1 can signal in the absence of DAF-4 kinase activity. A daf-1 mutation enhances dauer formation in a daf-4 null background, whereas overexpression of daf-1 partially rescues a daf-4 mutant. DAF-1 alone cannot fully compensate for the loss of DAF-4 activity, indicating that nondauer development normally results from the activities of both receptors. DAF-1 signaling in the absence of a type II kinase is unique in the type I receptor family. The activity may be an evolutionary remnant, owing to daf-1's origin near the type I/type II divergence, or it may be an innovation that evolved in nematodes. daf-1 and daf-4 promoters both mediated expression of green fluorescent protein in the nervous system, indicating that a DAF-1/DAF-4 receptor complex may activate a neuronal signaling pathway. Signaling from a strong DAF-1/DAF-4 receptor complex or a weaker DAF-1 receptor alone may provide larvae with more precise control of the dauer/nondauer decision in a range of environmental conditions.

scholarly journals Activin B Induces Noncanonical SMAD1/5/8 Signaling via BMP Type I Receptors in Hepatocytes: Evidence for a Role in Hepcidin Induction by Inflammation in Male Mice

Endocrinology ◽  
2016 ◽  
Vol 157 (3) ◽  
pp. 1146-1162 ◽  
Author(s):  
Susanna Canali ◽  
Amanda B. Core ◽  
Kimberly B. Zumbrennen-Bullough ◽  
Maria Merkulova ◽  
Chia-Yu Wang ◽  
...  
Keyword(s):  
Cell Types ◽  
Similar Degree ◽  
Type I ◽  
Activin Receptor ◽  
Hepcidin Expression ◽  
Morphogenetic Protein ◽  
Low Concentrations ◽  
Receptor Like Kinase ◽  
Anemia Of Inflammation

Abstract Induction of the iron regulatory hormone hepcidin contributes to the anemia of inflammation. Bone morphogenetic protein 6 (BMP6) signaling is a central regulator of hepcidin expression in the liver. Recently, the TGF-β/BMP superfamily member activin B was implicated in hepcidin induction by inflammation via noncanonical SMAD1/5/8 signaling, but its mechanism of action and functional significance in vivo remain uncertain. Here, we show that low concentrations of activin B, but not activin A, stimulate prolonged SMAD1/5/8 signaling and hepcidin expression in liver cells to a similar degree as canonical SMAD2/3 signaling, and with similar or modestly reduced potency compared with BMP6. Activin B stimulates hepcidin via classical activin type II receptors ACVR2A and ACVR2B, noncanonical BMP type I receptors activin receptor-like kinase 2 and activin receptor-like kinase 3, and SMAD5. The coreceptor hemojuvelin binds to activin B and facilitates activin B-SMAD1/5/8 signaling. Activin B-SMAD1/5/8 signaling has some selectivity for hepatocyte-derived cells and is not enabled by hemojuvelin in other cell types. Liver activin B mRNA expression is up-regulated in multiple mouse models of inflammation associated with increased hepcidin and hypoferremia, including lipopolysaccharide, turpentine, and heat-killed Brucella abortus models. Finally, the activin inhibitor follistatin-315 blunts hepcidin induction by lipopolysaccharide or B. abortus in mice. Our data elucidate a novel mechanism for noncanonical SMAD activation and support a likely functional role for activin B in hepcidin stimulation during inflammation in vivo.

scholarly journals Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling

Blood ◽  
2012 ◽  
Vol 120 (2) ◽  
pp. 431-439 ◽  
Author(s):  
Céline Besson-Fournier ◽  
Chloé Latour ◽  
Léon Kautz ◽  
Jessica Bertrand ◽  
Tomas Ganz ◽  
...  
Keyword(s):  
Underlying Disease ◽  
Type I ◽  
Protein Signaling ◽  
Regulatory Peptide ◽  
Primary Hepatocytes ◽  
Hepcidin Expression ◽  
Morphogenetic Protein ◽  
Receptor Like Kinase ◽  
Inflammatory Stimuli ◽  
Anemia Of Inflammation

Abstract Anemia is very common in patients suffering from infections or chronic inflammation and can add substantially to the morbidity of the underlying disease. It is mediated by excessive production of the iron-regulatory peptide hepcidin, but the signaling pathway responsible for hepcidin up-regulation in the inflammatory context is still not understood completely. In the present study, we show that activin B has an unexpected but crucial role in the induction of hepcidin by inflammation. There is a dramatic induction of Inhbb mRNA, encoding the activin βB-subunit, in the livers of mice challenged with lipopolysaccharide, slightly preceding an increase in Smad1/5/8 phosphorylation and Hamp mRNA. Activin B also induces Smad1/5/8 phosphorylation in human hepatoma–derived cells and, synergistically with IL-6 and STAT-3 signaling, up-regulates hepcidin expression markedly, an observation confirmed in mouse primary hepatocytes. Pretreatment with a bone morphogenic protein type I receptor inhibitor showed that the effect of activin B on hepcidin expression is entirely attributable to its effect on bone morphogenetic protein signaling, most likely via activin receptor-like kinase 3. Activin B is therefore a novel and specific target for the treatment of anemia of inflammation.

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