scholarly journals Structure of the Repulsive Guidance Molecule (RGM)–Neogenin Signaling Hub

Science ◽  
2013 ◽  
Vol 341 (6141) ◽  
pp. 77-80 ◽  
Author(s):  
Christian H. Bell ◽  
Eleanor Healey ◽  
Susan van Erp ◽  
Benjamin Bishop ◽  
Chenxiang Tang ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Cellular Processes ◽  
Autocatalytic Cleavage ◽  
Unknown Protein ◽  
Surface Receptor ◽  
Repulsive Guidance Molecule ◽  
Guidance Molecule ◽  
Multiple Signaling

Repulsive guidance molecule family members (RGMs) control fundamental and diverse cellular processes, including motility and adhesion, immune cell regulation, and systemic iron metabolism. However, it is not known how RGMs initiate signaling through their common cell-surface receptor, neogenin (NEO1). Here, we present crystal structures of the NEO1 RGM-binding region and its complex with human RGMB (also called dragon). The RGMB structure reveals a previously unknown protein fold and a functionally important autocatalytic cleavage mechanism and provides a framework to explain numerous disease-linked mutations in RGMs. In the complex, two RGMB ectodomains conformationally stabilize the juxtamembrane regions of two NEO1 receptors in a pH-dependent manner. We demonstrate that all RGM-NEO1 complexes share this architecture, which therefore represents the core of multiple signaling pathways.

scholarly journals Dectin-1-Mediated Production of Pro-Inflammatory Cytokines Induced by Yeast β-Glucans in Bovine Monocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana R. V. Pedro ◽  
Tânia Lima ◽  
Ricardo Fróis-Martins ◽  
Bárbara Leal ◽  
Isabel C. Ramos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Surface ◽  
Inflammatory Cytokines ◽  
Surface Expression ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Feed Supplements ◽  
Surface Receptor ◽  
Dose Dependent ◽  
Pro Inflammatory Cytokines

Yeast-derived products containing β-glucans have long been used as feed supplements in domesticated animals in an attempt to increase immunity. β-glucans are mainly recognized by the cell surface receptor CLEC7A, also designated Dectin-1. Although the immune mechanisms elicited through Dectin-1 activation have been studied in detail in mice and humans, they are poorly understood in other species. Here, we evaluated the response of bovine monocytes to soluble and particulate purified β-glucans, and also to Zymosan. Our results show that particulate, but not soluble β-glucans, can upregulate the surface expression of costimulatory molecules CD80 and CD86 on bovine monocytes. In addition, stimulated cells increased production of IL-8 and of TNF, IL1B, and IL6 mRNA expression, in a dose-dependent manner, which correlated positively with CLEC7A gene expression. Production of IL-8 and TNF expression decreased significantly after CLEC7A knockdown using two different pairs of siRNAs. Overall, we demonstrated here that bovine monocytes respond to particulate β-glucans, through Dectin-1, by increasing the expression of pro-inflammatory cytokines. Our data support further studies in cattle on the induction of trained immunity using dietary β-glucans.

scholarly journals Leptospiral Endostatin-Like Protein A Is a Bacterial Cell Surface Receptor for Human Plasminogen

2010 ◽  
Vol 78 (5) ◽  
pp. 2053-2059 ◽  
Author(s):  
Ashutosh Verma ◽  
Catherine A. Brissette ◽  
Amy A. Bowman ◽  
Samir T. Shah ◽  
Peter F. Zipfel ◽  
...  
Keyword(s):  
Binding Sites ◽  
Protein A ◽  
Aminocaproic Acid ◽  
Factor H ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Public Health Importance ◽  
Amino Terminal ◽  
Surface Receptor ◽  
Human Plasminogen

ABSTRACT The spirochete Leptospira interrogans is a highly invasive pathogen of worldwide public health importance. Studies from our laboratories and another have demonstrated that L. interrogans can acquire host plasminogen on its surface. Exogenous plasminogen activators can then convert bound plasminogen into the functionally active protease plasmin. In this study, we extend upon those observations and report that leptospiral endostatin-like protein A (LenA) binds human plasminogen in a dose-dependent manner. LenA-plasminogen interactions were significantly inhibited by the lysine analog ξ-aminocaproic acid, suggesting that the lysine-binding sites on the amino-terminal kringle portion of the plasminogen molecule play a role in the binding. Previous studies have shown that LenA also binds complement regulator factor H and the extracellular matrix component laminin. Plasminogen competed with both factor H and laminin for binding to LenA, which suggests overlapping ligand-binding sites on the bacterial receptor. Finally, LenA-bound plasminogen could be converted to plasmin, which in turn degraded fibrinogen, suggesting that acquisition of host-derived plasmin by LenA may aid bacterial dissemination throughout host tissues.

scholarly journals Comprehensive Analysis of the Prognostic Value and Immune Infiltration of Calpains in Pancreatic Cancer

2021 ◽  
Author(s):  
Lan Chuan ◽  
Haoyou Tang ◽  
Sheng Liu ◽  
Lin Ma ◽  
Yifu Hou
Keyword(s):  
Pancreatic Cancer ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Cell Surface Receptor ◽  
Cell Junction ◽  
Expression Levels ◽  
Surface Receptor

Abstract Background: Calpains (CAPNs) are intracellular calcium-activated neutral cysteine proteinases that are involved in cancer initiation, progression, and metastasis; however, their role in pancreatic cancer (PC) remains unclear. Methods: We combined data from various mainstream databases (i.e., Oncomine, GEPIA, Kaplan-Meier plotter, cBioPortal, STRING, GeneMANIA, and ssGSEA) and investigated the role of CAPNs in the prognosis of PC and immune cell infiltration.Results: Our results showed that CAPN1, 2, 4, 5, 6, 8, 9, 10, and 12 were highly expressed in PC. The expression levels of CAPN1, 5, 8, and 12 were positively correlated with the individual cancer stages. Moreover, the expression levels of CAPN1, 2, 5, and 8 were negatively correlated with the overall survival (OS) and recurrence-free survival (RFS); whereas that of CAPN10 was positively correlated with OS and RFS. We found that CAPN1, 2, 5, and 8 were correlated with tumour-infiltrating T follicular helper cells and CAPN10 with tumour-infiltrating T helper 2 cells. Functional enrichment analysis showed that the differentially expressed CAPNs (CAPN1, 2, 5, 8, and 10) are involved in axonogenesis, cell-substrate adhesion, immune response-activating cell surface receptor signalling pathway, and cell junction organisation in PC.Conclusions: These results suggested that CAPN1, 2, 5, 8, and 10 could be used as prognostic biomarkers in PC and can assist in improving individualised treatment strategies.

Regulation of c-ret expression by retinoic acid in rat metanephros: implication in nephron mass control

1998 ◽  
Vol 275 (6) ◽  
pp. F938-F945 ◽  
Author(s):  
Evelyne Moreau ◽  
José Vilar ◽  
Martine Lelièvre-Pégorier ◽  
Claudie Merlet-Bénichou ◽  
Thierry Gilbert
Keyword(s):  
Retinoic Acid ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Mrna Level ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
All Trans Retinoic Acid ◽  
Surface Receptor ◽  
Dose Dependent

Vitamin A and its derivatives have been shown to promote kidney development in vitro in a dose-dependent fashion. To address the molecular mechanisms by which all- trans-retinoic acid (RA) may regulate the nephron mass, rat kidneys were removed on embryonic day 14( E14) and grown in organ culture under standard or RA-stimulated conditions. By using RT-PCR, we studied the expression of the glial cell line-derived neurotrophic factor (GDNF), its cell surface receptor-α (GDNFR-α), and the receptor tyrosine kinase c-ret, known to play a major role in renal organogenesis. Expression of GDNF and GDNFR-α transcripts was high at the time of explantation and remained unaffected in culture with or without RA. In contrast, c-ret mRNA level, which was low in E14 metanephros and dropped rapidly in vitro, was increased by RA in a dose-dependent manner. The same is true at the protein level. Exogenous GDNF barely promotes additional nephron formation in vitro. Thus the present data establish c-ret as a key target of retinoids during kidney organogenesis.

scholarly journals Activation of membrane-bound proteins and receptor systems: a link between tissue kallikrein and the KLK-related peptidases

2014 ◽  
Vol 395 (9) ◽  
pp. 977-990 ◽  
Author(s):  
Ying Dong ◽  
Brittney S. Harrington ◽  
Mark N. Adams ◽  
Andreas Wortmann ◽  
Sally-Anne Stephenson ◽  
...  
Keyword(s):  
Cell Surface ◽  
Expression Profiles ◽  
Cell Surface Receptor ◽  
Specific Expression ◽  
Cellular Processes ◽  
Proteinase Activated Receptors ◽  
Surface Receptor ◽  
Membrane Bound ◽  
Multiple Receptor ◽  
Hepatocyte Growth

Abstract The 15 members of the kallikrein-related serine peptidase (KLK) family have diverse tissue-specific expression profiles and roles in a range of cellular processes, including proliferation, migration, invasion, differentiation, inflammation and angiogenesis that are required in both normal physiology as well as pathological conditions. These roles require cleavage of a range of substrates, including extracellular matrix proteins, growth factors, cytokines as well as other proteinases. In addition, it has been clear since the earliest days of KLK research that cleavage of cell surface substrates is also essential in a range of KLK-mediated cellular processes where these peptidases are essentially acting as agonists and antagonists. In this review we focus on these KLK-regulated cell surface receptor systems including bradykinin receptors, proteinase-activated receptors, as well as the plasminogen activator, ephrins and their receptors, and hepatocyte growth factor/Met receptor systems and other plasma membrane proteins. From this analysis it is clear that in many physiological and pathological settings KLKs have the potential to regulate multiple receptor systems simultaneously; an important issue when these peptidases and substrates are targeted in disease.

scholarly journals Symbiotic root infections in Medicago truncatula require remorin-mediated receptor stabilization in membrane nanodomains

2018 ◽  
Vol 115 (20) ◽  
pp. 5289-5294 ◽  
Author(s):  
Pengbo Liang ◽  
Thomas F. Stratil ◽  
Claudia Popp ◽  
Macarena Marín ◽  
Jessica Folgmann ◽  
...  
Keyword(s):  
Host Cell ◽  
Medicago Truncatula ◽  
Molecular Mechanisms ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Cell Infection ◽  
Molecular Scaffold ◽  
Rhizobial Inoculation ◽  
Surface Receptor ◽  
Functional Relevance

Plant cell infection is tightly controlled by cell surface receptor-like kinases (RLKs). Like other RLKs, the Medicago truncatula entry receptor LYK3 laterally segregates into membrane nanodomains in a stimulus-dependent manner. Although nanodomain localization arises as a generic feature of plant membrane proteins, the molecular mechanisms underlying such dynamic transitions and their functional relevance have remained poorly understood. Here we demonstrate that actin and the flotillin protein FLOT4 form the primary and indispensable core of a specific nanodomain. Infection-dependent induction of the remorin protein and secondary molecular scaffold SYMREM1 results in subsequent recruitment of ligand-activated LYK3 and its stabilization within these membrane subcompartments. Reciprocally, the majority of this LYK3 receptor pool is destabilized at the plasma membrane and undergoes rapid endocytosis in symrem1 mutants on rhizobial inoculation, resulting in premature abortion of host cell infections. These data reveal that receptor recruitment into nanodomains is indispensable for their function during host cell infection.

scholarly journals Soluble TREM2 induces inflammatory responses and enhances microglial survival

2017 ◽  
Vol 214 (3) ◽  
pp. 597-607 ◽  
Author(s):  
Li Zhong ◽  
Xiao-Fen Chen ◽  
Tingting Wang ◽  
Zhe Wang ◽  
Chunyan Liao ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Morphological Changes ◽  
Cell Surface Receptor ◽  
Soluble Form ◽  
Dependent Manner ◽  
Soluble Trem2 ◽  
Surface Receptor ◽  
The Brain ◽  
Ad Therapy

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB. Variants of sTREM2 carrying AD risk-associated mutations were less potent in both suppressing apoptosis and triggering inflammatory responses. Importantly, sTREM2 delivered to the hippocampi of both wild-type and Trem2-knockout mice elevated the expression of inflammatory cytokines and induced morphological changes of microglia. Collectively, these data indicate that sTREM2 triggers microglial activation inducing inflammatory responses and promoting survival. This study has implications for the pathogenesis of AD and provides insights into targeting sTREM2 pathway for AD therapy.

scholarly journals Proteomic Characterization of the Cellular Effects of AhR Activation by Microbial Tryptophan Catabolites in Endotoxin-Activated Human Macrophages

2021 ◽  
Vol 18 (19) ◽  
pp. 10336
Author(s):  
Katharina Walter ◽  
Henning Grosskopf ◽  
Isabel Karkossa ◽  
Martin von Bergen ◽  
Kristin Schubert
Keyword(s):  
Bacterial Infections ◽  
Immune Cell ◽  
Dependent Manner ◽  
Cellular Effects ◽  
Cellular Processes ◽  
Commensal Microbiota ◽  
Aryl Hydrocarbon ◽  
Tryptophan Metabolites ◽  
Tryptophan Catabolites

Sensing microbial tryptophan catabolites by the aryl hydrocarbon receptor (AhR) plays a pivotal role in host-microbiome homeostasis by modulating the host immune response. Nevertheless, the involved cellular processes triggered by the metabolites are mainly unknown. Here, we analyzed proteomic changes in macrophages after treatment with the tryptophan metabolites indole-3-acetic acid (I3AA) or indole-3-aldehyde (IAld), as well as the prototypic exogenous AhR-ligand benzo(a)pyrene (BaP) in the absence and presence of lipopolysaccharide (LPS) to identify affected cellular processes and pathways. The AhR-ligands regulated metabolic and immunologic processes in dependency of LPS co-stimulation. All investigated ligands time-dependently enhanced fatty acid β-oxidation. Differences due to the combination with LPS were observed for all three ligands. Additionally, oxidative phosphorylation was significantly increased by IAld and I3AA in a time and LPS-dependent manner. Immunoregulatory processes were affected in distinct ways. While BaP and I3AA up-regulated IL-8 signaling, IL-6 signaling was decreased by IAld. BaP decreased the inflammasome pathway. Thus, AhR-ligand-dependent regulations were identified, which may modulate the response of macrophages to bacterial infections, but also the commensal microbiota through changes in immune cell signaling and metabolic pathways that may also alter functionality. These findings highlight the relevance of AhR for maintaining microbial homeostasis and, consequently, host health.

scholarly journals A single dose of antibody-drug conjugate cures a stage 1 model of African trypanosomiasis

2019 ◽  
Author(s):  
Paula MacGregor ◽  
Andrea L. Gonzalez-Munoz ◽  
Fatoumatta Jobe ◽  
Martin C. Taylor ◽  
Steven Rust ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Antibody Drug Conjugate ◽  
African Trypanosomes ◽  
Drug Conjugate ◽  
Wide Range ◽  
Surface Receptor ◽  
Stage 1 ◽  
Antibody Drug

AbstractInfections of humans and livestock with African trypanosomes are treated with drugs introduced decades ago that are not always fully effective and often have severe side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has been exploited as a route of uptake for an antibody-drug conjugate (ADC) that is completely effective against Trypanosoma brucei in the standard mouse model of infection. Recombinant human anti-HpHbR monoclonal antibodies were isolated and shown to be internalised in a receptor-dependent manner. Antibodies were conjugated to a pyrrolobenzodiazepine (PBD) toxin and killed T. brucei in vitro at picomolar concentrations. A single therapeutic dose (0.25 mg/kg) of a HpHbR antibody-PBD conjugate completely cured a T. brucei mouse infection within 2 days with no re-emergence of infection over a subsequent time course of 77 days. These experiments provide a demonstration of how ADCs can be exploited to treat protozoal diseases that desperately require new therapeutics.Author SummaryHere we show that antibody-drug conjugates (ADCs) can be re-purposed from cancer immunotherapeutics to anti-protozoals by changing the specificity of the immunoglobulin to target a trypanosome cell surface receptor. Trypanosomes were used as a model system due to the availability of receptor null cell lines that allowed the unambiguous demonstration that ADCs targeted to a parasite surface receptor could be specifically internalised via receptor-mediated endocytosis. A single low dose of the resulting ADC was able to cure a stage 1 mouse model of trypanosome infection. We have used toxins and conjugation chemistry that are identical to anti cancer ADCs demonstrating the ability to piggy-back onto the huge research efforts and resources that are being invested in the development of such ADCs.The potential for development of ADCs against a wide range of human pathogens is vast, where only epitope binding sites need vary in order to provide selectivity. This provides a far-reaching opportunity for the rapid development of novel anti-protozoals for the targeted killing of a wide range of pathogens that cause disease worldwide, especially in developing countries.

scholarly journals Signaling activities of the Drosophila wingless gene are separately mutable and appear to be transduced at the cell surface.

Genetics ◽  
1995 ◽  
Vol 139 (1) ◽  
pp. 309-320 ◽  
Author(s):  
A Bejsovec ◽  
E Wieschaus
Keyword(s):  
Cell Surface ◽  
Function Analysis ◽  
Positional Information ◽  
Cell Surface Receptor ◽  
Intercellular Signaling ◽  
Cellular Processes ◽  
Complex Interactions ◽  
Segment Polarity ◽  
Surface Receptor ◽  
Segment Polarity Gene

Abstract The Drosophila segment polarity gene wingless encodes an intercellular signaling molecule that transmits positional information during development of the embryonic epidermis. We have explored the mechanism of wg signal transduction by perturbing cellular processes genetically and by performing structure/function analysis of the Wg protein. We present evidence that Wingless protein may transduce signal at the cell surface and that Wg may bind to its cell surface receptor without necessarily activating it. We demonstrate that two specific signaling activities of the Wg molecule can be disrupted independently by mutation. Sequence analysis indicates that these different signaling activities are not promoted by discrete functional domains, but rather than the overall conformation of the molecule may control distinct signaling functions. We conclude that wg signaling may involve complex interactions between the Wg ligand and its cell surface receptor molecule(s) and that some of this complexity resides within the Wg ligand itself.

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