Family Of Cell Adhesion Molecules Research Articles

Increased sensitivity to psychostimulants and GABAergic drugs in Lsamp-deficient mice

Lsamp, in combinations with other members of the IgLON family of cell adhesion molecules, promotes and inhibits neurite outgrowth and synapse formation during development. Mice lacking Lsamp gene display decreased social behaviour, hyperactivity; decreased anxiety level, alongside with altered balance in GABAA receptor α1 and α2 subunits; and decreased sensitivity to amphetamine, alongside with elevated serotonin function. In human studies, Lsamp has been associated with several psychiatric diseases, including schizophrenia, and suicide. Here, we provide a more thorough characterization of the pharmacological phenotype of Lsamp-deficient mice, including testing for sensitivity to morphine, cocaine, MK-801 and ketamine. More thorougly, sensitivity to GABA modulators (diazepam, alprazolam, ethanol, pentobarbital, TP003, and SL651498) was assessed. In brief, Lsamp-deficient mice were more sensitive to the locomotor activating effects of cocaine and morphine, and hypersensitive to the sedative and muscle relaxant effects of GABA modulators, most likely reflecting enhanced function of α1 and α5 subunits of the GABAA receptor. No gross differences in sensitivity to NMDA receptor modulators were observed. Thus, as the lack of Lsamp gene leads to widespread imbalances in major neurotransmitter systems in the brain accompanied by remarkable changes in behavioural phenotype as well, Lsamp-deficient mice are a promising model for mimicking psychiatric disorders.

Epidermis-Derived L1CAM Homolog Neuroglian Mediates Dendrite Enclosure and Blocks Heteroneuronal Dendrite Bundling

Building sensory dendritic arbors requires branching, growth, spacing, and substrate support. The conserved L1CAM family of cell-adhesion molecules generates neuronal isoforms to regulate neurite development in various aspects. However, whether non-neuronal isoforms participate in any of these aspects is unclear. In Drosophila, the L1CAM homolog Neuroglian (Nrg) is expressed as two isoforms: the neuronal isoform Nrg180 on dendritic surfaces of dendritic arborization (da) neurons and the non-neuronal isoform Nrg167 in epidermis innervated by dendrites. We found that epidermal Nrg167 encircles dendrites by interactions with dendritic Nrg180 to support dendrite growth, stabilization, and enclosure inside epidermis. Interestingly, whereas Nrg180 forms homophilic interactions to facilitate axonal bundling, heteroneuronal dendrites in the same innervating field avoid bundling through unknown mechanisms to maintain individual dendritic patterns. Here, we show that both epidermal Nrg167 depletion and neuronal Nrg180 overexpression can cause dendrite bundling, with genetic analyses suggesting that Nrg167-Nrg180 interactions antagonize Nrg180-Nrg180 homophilic interaction to prevent dendrite bundling. Furthermore, internalization of Nrg180 also participates in resolving dendrite bundling, as overexpression of endocytosis-defective Nrg180 and compromising endocytosis in neurons both exacerbated dendrite-bundling defects. Together, our study highlights the functional significance of substrate-derived Nrg167 in conferring dendrite stability, positioning, and avoidance.

Roles of integrin in tumor development and the target inhibitors

Integrin is a large family of cell adhesion molecules (CAMs) which involves in the interaction of cells/cells and cells/ extracellular matrix (ECM) to mediate cell proliferation, differentiation, adhesion, migration, etc. In recent years, aberrant expression of integrin has been clearly found in many tumor studies, indicating that integrin is closely related to tumor formation and development. Meanwhile, it has effects on tumor cell differentiation, cell migration, proliferation and tumor neovascularization. The study of drugs targeting integrins is of great significance for the clinical treatment of tumors. Because of its important role in tumorigenesis and development, integrin has become a promising target for the treatment of cancer. This review summarizes the role of integrin in tumor development and the current state of integrin inhibitors to provide a valuable reference for subsequent research.

Nectin-1 Expression in Colorectal Cancer: Is There a Group of Patients with High Risk for Early Disease Recurrence?

Background: Despite improvements in therapy of colorectal cancer, some patients will present occurrence of recurrence either locally or distantly. Tumor metastasis constitutes the major cause of cancer-associated morbidity and mortality. Nectin-1 belongs to the family of immunoglobulin-like cell adhesion molecules that contribute to the formation of cell-cell adhesions and regulate a series of cellular activities including cell polarization, differentiation, movement, proliferation, and survival. Expression of Nectin-1 in malignant tumors has been associated with aggressive tumor phenotypes. Objectives: The aim of the present study was to assess Nectin-1 expression patterns in colorectal cancer and to investigate its clinical significance. Methods: Nectin-1 expression was assessed via immunohistochemistry in surgical specimens of a cohort comprised of 111 patients with primary resectable colorectal cancer. Results were correlated with clinicopathological characteristics and survival data. Progression-free survival was defined as the primary outcome of the present study. Results: Nectin-1 was strongly expressed in the cytoplasm of colorectal cancer cells. High Nectin-1 expression was associated with advanced stage of disease (p = 0.012) and lymph node metastasis (p = 0.007). Progression-free survival of patients exhibiting high expression of Nectin-1 in the first 36 months after surgery was significantly worse compared to patients with low expression of Nectin-1 (55.7%, 95% CI = 47–70, vs. 82.1%, 95% CI = 69–93, p = 0.014) and independent of other clinicopathological characteristics (HR = 0.389, 95% CI = 0.156–0.972, p = 0.043). Conclusion: Nectin-1 expression in colorectal cancer is associated with a significantly worse 3-year progression-free survival identifying therefore a group of patients with high risk for early disease recurrence.

Aberrant expression of CHL1 gene and long non-coding RNA CHL1-AS1, CHL1-AS2 in ovarian endometriosis

Objective(s)CHL1 (close homologue of L1 or cell adhesion molecule L1 like), also referred as CALL, is a member of the L1 gene family of neural cell adhesion molecules and belongs to immunoglobulin superfamily. This study aims to investigate the potential correlation of the CHL1 gene and the long non-coding RNAs (lncRNAs), i.e., CHL1-AS1 and CHL1-AS2, and to validate the expression patterns of CHL1 and CHL1-AS2 in ovarian endometriosis (EM). Study designOur previous microarray analyses (GSE86534) of 4 patients with ovarian EM indicated that CHL1 was the most upregulated mRNA in ectopic endometrium (EC) compared with eutopic endometrium (EU) tissues, and that its two antisense lncRNAs CHL1-AS1 and CHL1-AS2, exhibited the same expression pattern. We used a bioinformatics-based strategy to calculate the correlation among CHL1, CHL1-AS1 and CHL1-AS2. Gene set enrichment analysis (GSEA) was performed to analyze commonly enriched gene sets for CHL1-AS1 and CHL1-AS2. Using quantitative real-time polymerase chain reaction (qPCR), we examined the expression levels of CHL1 mRNA and lncRNA CHL1-AS2 in paired tissues of EC and EU from 30 EM patients and normal endometrium (NE) tissues from 27 controls using quantitative real-time polymerase chain reaction (qPCR). We also examined the expression of CHL1 protein in EC, EU and NE tissues using western blotting and immunohistochemistry (IHC). ResultsCHL1, CHL1-AS1 and CHL1-AS2 were significantly correlated with each other given that the Pearson correlation values were > 0.9 using bioinformatic calculation. GSEA revealed that CHL1-AS1 and CHL1-AS2 were negatively associated with the same gene set “WAMUNYOKOLI_OVARIAN_CANCER_LMP”. qPCR confirmed that the CHL1 and CHL1-AS2 expression levels were significantly higher in EC tissues than in EU and NE tissues, while they were not significantly different in EU compared with NE tissues. The relative expression levels of CHL1 and CHL1-AS2 in EC compared with EU tissues were positively significantly correlated (Pearson correlation coefficient = 0.421 and P value = 0.02). Elevated expression of CHL1 protein in EC tissues was detected by western blotting. IHC revealed that CHL1 protein expression levels enhanced in ectopic endometrial glands and stroma. Conclusion(s)Our results indicate a significant correlation among CHL1, CHL1-AS1 and CHL1-AS2, which might be involved in the development of ovarian EM and serve as novel targets for future research.

Subcellular localization of mutated β-catenins with different incidences of cis-peptide bonds at the Xaa246-P247 site in HepG2 cells.

Mutations may ultimately change the local conformation of proteins; however, little attention has been paid to alterations in protein function caused by the incidence of cis-peptide bonds (ICPB) in mammalian cells. In this study, a statistical approach, coimmunoprecipitation, and immunofluorescence staining have been used to confirm that S246→Y and S246→W missense mutations, which help increase the ICPB in Xaa246-P247 (Xaa is any amino acid) in human β-catenin, can reduce the interactions between β-catenin and adenomatous polyposis coli (APC) and between β-catenin and Ca2+-dependent cell adhesion molecule family in epithelial tissue (E-cadherin), eventually leading to increased nuclear migration of β-catenin in the HepG2 cell line (an immortalized cell line consisting of human liver carcinoma cells). Conversely, S246→L and S246→M missense mutations, which reduce the ICPB in Xaa246-P247 in human β-catenin, can enhance interactions between β-catenin and APC and between β-catenin and E-cadherin, leading to decreased nuclear migration of β-catenin. These results not only indicate that a change in the ICPB may be an important cause of functional protein changes but also provide a new basis for the study of genetic disease prediction, gene diagnosis, individualized treatment, and protein modification at the gene level for clinicians and other professionals.—Yu, S., Zhang, Y., Wu, Y., Yang, H., Chen, Y., Yang, Y., Zhang, Z. Subcellular localization of mutated β-catenins with different incidences of cis-peptide bonds at the Xaa246-P247 site in HepG2 cells.

Association of ICAM-1 gene variant rs5498 (1462A>G) with non-obstructive azoospermia

The blood testicular barrier (BTB) is a barrier protecting the testes from damage. It also plays an important role in spermatogenesis. The intracellular adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin cell adhesion molecule family and is a constituent component of the BTB. This study was carried out to investigate the association between the single nucleotide polymorphism (SNP) rs5498 in the ICAM-1 gene and non-obstructive azoospermia. A total of 100 male patients with non-obstructive azoospermia and 100 fertile males (healthy control) were included in this study. Genotyping of ICAM-1 gene rs5498 was performed using polymerase chain reaction-restriction enzyme fragment length polymorphism (PCR-RFLP). Both AG and GG genotypes were significantly more prevalent among the infertile men compared to the control group (p < 0.001). The odds ratio (OR) for the polymorphic allele (G) was 2.4 with 95% confidence interval from 1.38 to 3.19 (p < 0.001). The study shows that ICAM-1 rs5498 (1462A>G) SNP is positively associated with an increased risk for obstructive azoospermia, with the genotype AG heterozygotes showing a significantly higher frequency among infertile men.

Biomarkers of Acute Graft-Versus-Host Disease: Surface Antigens and Micro Rnas in Extracellular Vesicles

Introduction Biomarkers could be crucial to identify patients at high-risk of acute Graft-vs.-Host Disease (aGVHD). Given their involvement in inflammation, Extracellular Vesicles (EVs) may become attractive biomarkers. Moreover, EVs are non-invasively extracted from body fluids. In a preliminary study, we significantly correlated CD146, CD31 and CD140a expression on EVs membranes with the onset of aGVHD (Lia G. Leukemia 2017). Objectives We designed a prospective study to further characterize EVs by their surface antigens and by their content in MicroRNAs. Methods EVs are extracted from serum samples at given time-points (pre-transplant, on day 0, 3, 7, 14, 21, 28, 35, 45 and then monthly up to 1 year) by a protamine-based precipitation method and analyzed by flow-cytometry (Guava EasyCyte Flow Cytometer) for the expression of 13 membrane proteins (CD44, CD138, CD146, KRT18, CD120a, CD8, CD30, CD106, CD25, CD31, CD144, CD86, and CD140a). MicroRNAs (miR100, miR92b, miR155, miR194) are extracted from EVs at pre- transplant and on day 0, 7, 14, 28, and quantified by real time PCR as relative quantification compared to healthy donors after cDNA Reverse Transcription. Logistic Regression Analysis is performed for each marker. Results Thirty-five transplant patients with hematological diseases have so far been enrolled. Seventeen/35 patients (49%) developed grade II-IV aGVHD. Our preliminary findings show that CD146 (melanoma cell adhesion molecule, MCAM-1) and CD44 (homing-associated cell adhesion molecule, H-CAM) were associated with an increased risk of aGVHD (Odds Ratio (OR) 4.3, p=0.008; OR 2.1, p=0.039), whereas CD31 (platelet endothelial cell adhesion molecule, PECAM-1) level was associated with a decreased risk of aGVHD (OR 0.31, p=0.001). Moreover, increased risk of aGVHD was significantly correlated with levels of miR100 (OR 4.66, p=0.004), miR194 (OR 2.2, p=0.01) and miR155 (OR 3.56, p=0.035). Of note, biomarkers associated with aGVHD showed a constant consensual change in signal levels before aGVHD onset (Figure 1). Conclusions An association of 3 EVs membrane antigens and onset of aGVHD was observed. Of note, CD146, CD44 and CD31 belong to the Cell Adhesion Molecule Family and are critical for endothelium and immune cells interactions. The functional role of miR-194 in GVHD pathogenesis remains to be determined while JAK/STAT and TGFβ pathways were shown to be involved in other studies (Gimondi S Exp Hematol, 2016). MiR-100 has been reported to regulate inflammatory neovascularization during GvHD (Leonhardt F, Blood 2013) while miR-155 drives donor T cell expansion and tissue infiltration (Zitzer N, J Immunol 2018, Ranganathan P Blood 2012).

Organization of motor pools depends on the combined function of N-cadherin and type II cadherins.

Type I and type II classical cadherins constitute a family of cell adhesion molecules expressed in complex combinatorial profiles in the nervous system, suggesting that a cadherin code implements specific adhesive recognition events that control the development of neural circuits. In the spinal cord, classical cadherins define at a molecular level the positional organization of motor neuron subtypes into discrete nuclear structures termed motor pools. However, the roles and contributions of different members of the family in defining motor neuron spatial organization are not yet clear. By combining mouse genetics with quantitative positional analysis, we found that motor neuron organization into pools depends on type II cadherins. Type II cadherin function, however, does not strictly reflect the predictions arising from binding specificities at a molecular level, but instead relies on N-cadherin, a type I cadherin whose elimination is required to reveal type II contributions.

Kirrel2 is differentially required in populations of olfactory sensory neurons for the targeting of axons in the olfactory bulb.

The formation of olfactory maps in the olfactory bulb (OB) is crucial for the control of innate and learned mouse behaviors. Olfactory sensory neurons (OSNs) expressing a specific odorant receptor project axons into spatially conserved glomeruli within the OB and synapse onto mitral cell dendrites. Combinatorial expression of members of the Kirrel family of cell adhesion molecules has been proposed to regulate OSN axonal coalescence; however, loss-of-function experiments have yet to establish their requirement in this process. We examined projections of several OSN populations in mice that lacked either Kirrel2 alone, or both Kirrel2 and Kirrel3. Our results show that Kirrel2 and Kirrel3 are dispensable for the coalescence of MOR1-3-expressing OSN axons to the most dorsal region (DI) of the OB. In contrast, loss of Kirrel2 caused MOR174-9- and M72-expressing OSN axons, projecting to the DII region, to target ectopic glomeruli. Our loss-of-function approach demonstrates that Kirrel2 is required for axonal coalescence in subsets of OSNs that project axons to the DII region and reveals that Kirrel2/3-independent mechanisms also control OSN axonal coalescence in certain regions of the OB.

Fusobacterium spp. target human CEACAM1 via the trimeric autotransporter adhesin CbpF

ABSTRACTNeisseria meningitidis, Haemophilus influenzae, and Moraxella catarrhalis are pathogenic bacteria adapted to reside on human respiratory mucosal epithelia. One common feature of these species is their ability to target members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, especially CEACAM1, which is achieved via structurally distinct ligands expressed by each species. Beside respiratory epithelial cells, cells at the dentogingival junction express high levels of CEACAM1. It is possible that bacterial species resident within the oral cavity also utilise CEACAM1 for colonisation and invasion of gingival tissues. From a screen of 59 isolates from the human oral cavity representing 49 bacterial species, we identified strains from Fusobacterium bound to CEACAM1. Of the Fusobacterium species tested, the CEACAM1-binding property was exhibited by F. nucleatum (Fn) and F. vincentii (Fv) but not F. polymorphum (Fp) or F. animalis (Fa) strains tested. These studies identified that CEACAM adhesion was mediated using a trimeric autotransporter adhesin (TAA) for which no function has thus far been defined. We therefore propose the name CEACAM binding protein of Fusobacterium (CbpF). CbpF was identified to be present in the majority of unspeciated Fusobacterium isolates confirming a subset of Fusobacterium spp. are able to target human CEACAM1.

Increased L1CAM (CD171) levels are associated with glioblastoma and metastatic brain tumors.

L1 cell adhesion molecule (L1CAM) is a member of the immunoglobulin-like cell-adhesion molecule family that was shown to be associated with a worse prognosis in several human cancers. L1 ectodomain shedding via vesicles or exosomes has been detected in extracellular fluids after cleavage from the cell surface by metalloproteases. We evaluated the presence of L1CAM in cyst fluid and tissue from glioblastomas or brain metastases.The amount of L1CAM in cyst fluid of 9 glioblastomas and 11 brain metastases was assessed using enzyme-linked immunosorbent assay (ELISA). Corresponding tumor tissue slices were stained immunohistochemically for L1CAM. Cerebrospinal fluid of 20 non-tumor patients served as controls.Mean levels of L1CAM in tumor cyst fluid were significantly higher in glioblastoma (6118 ± 4095 ng/mL) and metastasis patients (8001 ± 6535 ng/mL) than in CSF of control patients (714 ± 22 ng/mL). The immunohistochemical expression of L1CAM in corresponding tissue was significantly higher in metastases than in glioblastomas.The present study demonstrates high levels of L1CAM in cyst fluid of glioblastoma and metastatic brain tumors. Soluble L1CAM may represent a motility promoting molecule in cancer progression, a co-factor for development of tumor cysts and a target for new treatment strategies.

Early-life stress impairs developmental programming in Cadherin 13 (CDH13)-deficient mice

ObjectiveCadherin-13 (CDH13), a member of the calcium-dependent cell adhesion molecule family, has been linked to neurodevelopmental disorders, including autism spectrum (ASD) and attention-deficit/hyperactivity (ADHD) disorders, but also to depression. In the adult brain, CDH13 expression is restricted e.g. to the presynaptic compartment of inhibitory GABAergic synapses in the hippocampus and Cdh13 knockout mice show an increased inhibitory drive onto hippocampal CA1 pyramidal neurons, leading to a shift in excitatory/inhibitory balance. CDH13 is also moderating migration of serotonergic neurons in the dorsal raphe nucleus, establishing projections preferentially to the thalamus and cerebellum during brain development. Furthermore, CDH13 is upregulated by chronic stress as well as in depression, suggesting a role in early-life adaptation to stressful experience. Here, we therefore investigated the interaction between Cdh13 variation and neonatal maternal separation (MS) in mice. MethodsMale and female wild-type (Cdh13+/+), heterozygous (Cdh13+/−) and homozygous (Cdh13−/−) knockout mice exposed to MS, or daily handling as control, were subjected to a battery of behavioural tests to assess motor activity, learning and memory as well as anxiety-like behaviour. A transcriptome analysis of the hippocampus was performed in an independent cohort of mice which was exposed to MS or handling, but remained naïve for behavioural testing. ResultsMS lead to increased anxiety-like behaviour in Cdh13−/− mice compared to the other two MS groups. Cdh13−/− mice showed a context-dependent effect on stress- and anxiety-related behaviour, impaired extinction learning following contextual fear conditioning and decreased impulsivity, as well as a mild decrease in errors in the Barnes maze and reduced risk-taking in the light-dark transition test after MS. We also show sex differences, with increased locomotor activity in female Cdh13−/− mice, but unaltered impulsivity and activity in male Cdh13−/− mice. Transcriptome analysis revealed several pathways associated with cell surface/adhesion molecules to be altered following Cdh13 deficiency, together with an influence on endoplasmic reticulum function. ConclusionMS resulted in increased stress resilience, increased exploration and an overall anxiolytic behavioural phenotype in male Cdh13+/+ and Cdh13+/− mice. Cdh13 deficiency, however, obliterated most of the effects caused by early-life stress, with Cdh13−/− mice exhibiting delayed habituation, no reduction of anxiety-like behaviour and decreased fear extinction. Our behavioural findings indicate a role of CDH13 in the programming of and adaptation to early-life stress. Finally, our transcriptomic data support the view of CDH13 as a neuroprotective factor as well as a mediator in cell-cell interactions, with an impact on synaptic plasticity.

α-Neurexins Together with α2δ-1 Auxiliary Subunits Regulate Ca2+ Influx through Cav2.1 Channels.

Action potential-evoked neurotransmitter release is impaired in knock-out neurons lacking synaptic cell-adhesion molecules α-neurexins (αNrxns), the extracellularly longer variants of the three vertebrate Nrxn genes. Ca2+ influx through presynaptic high-voltage gated calcium channels like the ubiquitous P/Q-type (CaV2.1) triggers release of fusion-ready vesicles at many boutons. α2δ Auxiliary subunits regulate trafficking and kinetic properties of CaV2.1 pore-forming subunits but it has remained unclear if this involves αNrxns. Using live cell imaging with Ca2+ indicators, we report here that the total presynaptic Ca2+ influx in primary hippocampal neurons of αNrxn triple knock-out mice of both sexes is reduced and involved lower CaV2.1-mediated transients. This defect is accompanied by lower vesicle release, reduced synaptic abundance of CaV2.1 pore-forming subunits, and elevated surface mobility of α2δ-1 on axons. Overexpression of Nrxn1α in αNrxn triple knock-out neurons is sufficient to restore normal presynaptic Ca2+ influx and synaptic vesicle release. Moreover, coexpression of Nrxn1α together with α2δ-1 subunits facilitates Ca2+ influx further but causes little augmentation together with a different subunit, α2δ-3, suggesting remarkable specificity. Expression of defined recombinant CaV2.1 channels in heterologous cells validates and extends the findings from neurons. Whole-cell patch-clamp recordings show that Nrxn1α in combination with α2δ-1, but not with α2δ-3, facilitates Ca2+ currents of recombinant CaV2.1 without altering channel kinetics. These results suggest that presynaptic Nrxn1α acts as a positive regulator of Ca2+ influx through CaV2.1 channels containing α2δ-1 subunits. We propose that this regulation represents an important way for neurons to adjust synaptic strength.SIGNIFICANCE STATEMENT Synaptic transmission between neurons depends on the fusion of neurotransmitter-filled vesicles with the presynaptic membrane, which subsequently activates postsynaptic receptors. Influx of calcium ions into the presynaptic terminal is the key step to trigger vesicle release and involves different subtypes of voltage-gated calcium channels. We study the regulation of calcium channels by neurexins, a family of synaptic cell-adhesion molecules that are essential for many synapse properties. Using optical measurements of calcium influx in cultured neurons and electrophysiological recordings of calcium currents from recombinant channels, we show that a major neurexin variant facilitates calcium influx through P/Q-type channels by interacting with their α2δ-1 auxiliary subunits. These results propose a novel way how neurons can modulate the strength of distinct synapses.

Systemic Inflammation Changes the Site of RAGE Expression from Endothelial Cells to Neurons in Different Brain Areas.

The receptor for advanced glycation endproducts (RAGE) is a transmembrane, immunoglobulin-like receptor that interacts with a broad repertoire of extracellular ligands. RAGE belongs to a family of cell adhesion molecules and is considered a key receptor in the inflammation axis and a potential contributor to the neurodegeneration. The present study aimed to investigate the content and cell localization of RAGE in the brain of Wistar rats subjected to systemic inflammation induced by a single dose of lipopolysaccharide (LPS, 5mg/kg, i.p.). Fifteen days after LPS administration, the content of RAGE was analyzed in the prefrontal cortex (PFC), hippocampus (HIPP), cerebellum (CB), and substantia nigra (SN) were investigated. RAGE levels increased in all structures, except HIPP; however, immunohistochemistry analysis demonstrated that the cell site of RAGE expression changed from blood vessel-like structures to neuronal cells in all brain areas. Besides, the highest level of RAGE expression was found in SN. Immunofluorescence analysis in SN confirmed that RAGE expression was mainly co-localized in endothelial cells (RAGE/PECAM-1 co-staining) in untreated animals, while LPS-treated animals had RAGE expression predominantly in dopaminergic neurons (RAGE/TH co-staining). Decreased TH levels, as well as increased pro-inflammatory markers (TNF-α, IL-1β, Iba-1, GFAP, and phosphorylated ERK1/2) in SN, occurred concomitantly to RAGE stimulation in the same site. These results suggest a role for RAGE in the establishment of a neuroinflammation-neurodegeneration axis that develops as a long-term response to systemic inflammation by LPS.

Quantitative Analysis of Interaction Between CADM1 and Its Binding Cell-Surface Proteins Using Surface Plasmon Resonance Imaging.

The cell adhesion molecule (CADM) family of the immunoglobulin superfamily (IgSF) comprises four members, CADM1–CADM4, and participates in the formation of epithelial and synaptic adhesion through cell–cell homophilic and heterophilic interactions. To identify the partners that interact with each member of the CADM family proteins, we set up a platform for multiple detection of the extracellular protein–protein interactions using surface plasmon resonance imaging (SPRi) and analyzed the interactions between the CADM family proteins and 10 IgSF of their structurally related cell adhesion molecules. SPRi analysis identified a new interaction between CADM1 and CADM4, where this heterophilic interaction was shown to be involved in morphological spreading of adult T-cell leukemia (ATL) cells expressing CADM1 when incubated on CADM4-coated glass. Moreover, class-I MHC-restricted T-cell-associated molecule (CRTAM) was identified to show the highest affinity to CADM1 among its binding partners by comparing the dissociation constants calculated from the SPR sensorgrams. These results suggest that the SPRi platform would provide a novel screening tool to characterize extracellular protein–protein interactions among cell-surface and secreted proteins, including IgSF molecules.

Brain proteomic differences between wild-type and CD44- mice induced by chronic Toxoplasma gondii infection.

Chronic clinical Toxoplasma gondii (T. gondii) infection is the primary disease state that causes severe encephalitis. CD44 is a member of the cell adhesion molecule family and plays an important role in T. gondii infection. However, proteomic changes in CD44 during chronic T. gondii infection have rarely been reported. Thus, an iTRAQ-based proteomic study coupled with 2D-LC-MS/MS analysis was performed to screen CD44-related proteins during chronic T. gondii infection. As a result, a total of 2612 proteins were reliably identified and quantified. Subsequently, 259, 106, and 249 differentially expressed proteins (DEPs) were compared between CD44- mice (A) vs wild-type mice (B), B vs wild-type mice infected with T. gondii (C), and C vs CD44- mice infected with T. gondii (D). Gene ontology, KEGG pathway, and protein-protein interaction analyses were performed on the DEPs. According to the results, immune-related proteins were altered significantly among the A vs B, B vs C, and C vs D comparisons, which might indicate that chronic T. gondiiinfection caused changes in the host immune response. Additionally, Ca2+- and metabolism-related proteins were upregulated in C vs D, which supported the hypothesis that CD44 mediated the production of host Ca2+ and IFN-γ and that the parasite preferentially invaded cells expressing high levels of CD44. The present findings validate and enable a more comprehensive knowledge of the role of CD44 in hosts chronically infected with T. gondii, thus providing new ideas for future studies on the specific functions of CD44 in latent toxoplasmosis.

Helicobacter pylori adhesin HopQ disrupts trans dimerization in human CEACAMs.

The human gastric pathogen Helicobacter pylori is a major causative agent of gastritis, peptic ulcer disease, and gastric cancer. Aspart of its adhesive lifestyle, the bacterium targets members ofthe carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family by the conserved outer membrane adhesin HopQ. The HopQ-CEACAM1 interaction is associated with inflammatory responses and enables the intracellular delivery and phosphorylation of the CagA oncoprotein via a yet unknown mechanism. Here, we generated crystal structures of HopQ isotypes I and II bound to the N-terminal domain of human CEACAM1 (C1ND) and elucidated the structural basis of H.pylori specificity toward human CEACAM receptors. Both HopQ alleles target the β-strands G, F, and C of C1ND, which form the trans dimerization interface in homo- and heterophilic CEACAM interactions. Using SAXS, we show that the HopQ ectodomain is sufficient to induce C1ND monomerization and thus providing H.pylori a route to influence CEACAM-mediated cell adherence and signaling events.

SALM/Lrfn Family Synaptic Adhesion Molecules.

Synaptic adhesion-like molecules (SALMs) are a family of cell adhesion molecules involved in regulating neuronal and synapse development that have also been implicated in diverse brain dysfunctions, including autism spectrum disorders (ASDs). SALMs, also known as leucine-rich repeat (LRR) and fibronectin III domain-containing (LRFN) proteins, were originally identified as a group of novel adhesion-like molecules that contain LRRs in the extracellular region as well as a PDZ domain-binding tail that couples to PSD-95, an abundant excitatory postsynaptic scaffolding protein. While studies over the last decade have steadily explored the basic properties and synaptic and neuronal functions of SALMs, a number of recent studies have provided novel insights into molecular, structural, functional and clinical aspects of SALMs. Here we summarize these findings and discuss how SALMs act in concert with other synaptic proteins to regulate synapse development and function.

RUNX transcription factors potentially control E-selectin expression in the bone marrow vascular niche in mice

AbstractAlthough the function of Runt-related (RUNX) transcription factors has been well characterized in leukemogenesis and regarded as an ideal target in antileukemia strategies, the effect of RUNX-inhibition therapy on bone marrow niche cells andr its impact on the engraftment of acute myeloid leukemia (AML) cells have largely been unknown. Here, we provide evidence suggesting the possible involvement of RUNX transcription factors in the transactivation of E-selectin, a member of selectin family of cell adhesion molecules, on the vascular endothelial cells of the mice bone marrow niche. In our experiments, gene switch-mediated silencing of RUNX downregulated E-selectin expression in the vascular niche and negatively controlled the engraftment of AML cells in the bone marrow, extending the overall survival of leukemic mice. Our work identified the novel role of RUNX family genes in the vascular niche and showed that the vascular niche, a home for AML cells, could be strategically targeted with RUNX-silencing antileukemia therapies. Considering the excellent efficacy of RUNX-inhibition therapy on AML cells themselves as we have previously reported, this strategy potentially targets AML cells both directly and indirectly, thus providing a better chance of cure for poor-prognostic AML patients.