NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor

Rasmussen, Kim Krighaar; Falkesgaard, Maria Hansen; Winther, Malene; Roed, Nikolaj Kulahin; Quistgaard, Christine Louise; Teisen, Marie Nygaard; Edslev, Sofie; Petersen, David L.; Aljubouri, Ali; Christensen, Christa Lykke; Thulstrup, Peter W.; Leggio, Leila Lo; Teilum, Kaare; Walmod, Peter S.

doi:10.1038/s41598-018-27089-7

Cited by 18 publications

(14 citation statements)

References 52 publications

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“…The extracellular domain of NCAM2 has been shown to bind to Aβ oligomers ( 42 ). The FN2 domain of NCAM2 could also bind and activate FGFR1, inducing neurite outgrowth ( 78 ). It is therefore possible that the sNCAM2 acts as a dominant negative by binding to membrane-bound NCAM2-FL or other binding partners to NCAM2.…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal processing of neural cell adhesion molecules 1 and 2 by BACE1 in vivo

Kim

Watanabe

Lomoio

et al. 2021

Journal of Biological Chemistry

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Neural cell adhesion molecules 1 (NCAM1) and 2 (NCAM2) belong to the cell adhesion molecules of the immunoglobulin superfamily and have been shown to regulate formation, maturation, and maintenance of synapses. NCAM1 and NCAM2 undergo proteolysis, but the identity of all the proteases involved and how proteolysis is used to regulate their functions are not known. We report here that NCAM1 and NCAM2 are BACE1 substrates in vivo . NCAM1 and NCAM2 overexpressed in HEK cells were both cleaved by metalloproteinases or BACE1, and NCAM2 was also processed by γ-secretase. We identified the BACE1 cleavage site of NCAM1 (at Glu 671) and NCAM2 (at Glu 663) using mass spectrometry and site-directed mutagenesis. Next, we assessed BACE1-mediated processing of NCAM1 and NCAM2 in the mouse brain during aging. NCAM1 and NCAM2 were cleaved in the olfactory bulb of BACE1+/+ but not BACE1−/− mice at postnatal day 10 (P10), 4 and 12 months of age. In the hippocampus, a BACE1-specific soluble fragment of NCAM1 (sNCAM1β) was only detected at P10. However, we observed an accumulation of full-length NCAM1 in hippocampal synaptosomes in 4-month-old BACE1−/− mice. We also found that polysialylated NCAM1 (PSA-NCAM1) levels were increased in BACE1−/− mice at P10 and demonstrated that BACE1 cleaves both NCAM1 and PSA-NCAM1 in vitro . In contrast, we did not find evidence for BACE1-dependent NCAM2 processing in the hippocampus at any age analyzed. In summary, our data demonstrate that BACE1 differentially processes NCAM1 and NCAM2 depending on the region of brain, subcellular localization, and age in vivo .

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Section: Discussionmentioning

confidence: 99%

Spatiotemporal processing of neural cell adhesion molecules 1 and 2 by BACE1 in vivo

Kim

Watanabe

Lomoio

et al. 2021

Journal of Biological Chemistry

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“…The TOMM6 gene has not been reported. NCAM2 is a close homolog of the neuronal cell adhesion molecule NCAM1 and stimulates neurite outgrowth through FGFR-dependent activation of the Ras/MAPK pathway (34,35). Several studies have reported that NCAM2 can be used as a new therapeutic target for cancer, especially prostate cancer and breast cancer (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

A signature of tumor immune microenvironment genes associated with the prognosis of non‑small cell lung cancer

Zhang

et al. 2020

Oncol Rep

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Establishing a prognostic genetic signature closely related to the tumor immune microenvironment (TIME) to predict clinical outcomes is necessary. Using the Gene Expression Omnibus (GEO) database of a non-small cell lung cancer (NSCLC) cohort and the immune score derived from the Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm, we applied the least absolute shrinkage and selection operator (LASSO) Cox regression model to screen a 10-gene signature among the 448 differentially expressed genes and found that the risk prediction models constructed by 10 genes could be more sensitive to prognosis than TNM (Tumor, Lymph node and Metastasis) stage (P=0.006). The CIBERSORT method was applied to quantify the relative levels of different immune cell types. It was found that the ratio of eosinophils, mast cells (MCs) resting and CD4 T cells memory activated in the low-risk group was higher than that in the high-risk group, and the difference was statistically significant (P= 0.003, P= 0.014 and P= 0.018, respectively). Inconsistently, the ratio of resting natural killer (NK) cells and activated plasma cells in the low-risk group was significantly lower than that in the high-risk group (P= 0.05 and P=0.009, respectively). Kaplan-Meier survival results showed that patients of the high-risk group had significantly shorter overall survival (OS) than those of the low-risk group in the training set (P<0.001). Furthermore, Kaplan-Meier survival showed that patients of the high-risk group had significantly shorter OS than those of the low-risk group (P=0.0025 and P=0.0157, respectively) in the validation set [GSE31210 and TCGA (The Cancer Genome Atlas)]. The 10-gene signature was found to be an independent risk factor for prognosis in univariate and multivariate Cox proportional hazard regression analyses (P<0.001). In addition, it was found that the risk model constructed by the 10-gene signature was related to the clinical related factors in logistic regression analysis. The genetic signature closely related to the immune microenvironment was found to be able to predict differences in the proportion of immune cells (eosinophils, resting MCs, memory activated CD4 T cells, resting NK cells and plasma cells) in the risk model. Our findings suggest that the genetic signature closely related to TIME could predict the prognosis of NSCLC patients, and provide some reference for immunotherapy.

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“…The imbalance in the expression levels of LRP1 in fibroblasts of healing tissues may lead to unlimited expansion of contractile fibroblasts, thus causing or aggravating pulmonary fibrosis and participating in the pathogenesis of asthma (Schnieder et al, 2019). Neural cell adhesion molecule 2 (NCAM2) protein has been shown to reduce inflammation in Alzheimer's disease (Rasmussen et al, 2018). CNTN1, which is also a cell adhesion protein, can promote the invasion of prostate cancer cells, enhance Akt activation, and reduce the expression of epithelial cadherin in cancer cells (Yan et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Differentially expressed serum proteins in children with or without asthma as determined using isobaric tags for relative and absolute quantitation proteomics

Qin

et al. 2020

PeerJ

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Background Although asthma is one of the most common chronic, noncommunicable diseases worldwide, the pathogenesis of childhood asthma is not yet clear. Genetic factors and environmental factors may lead to airway immune-inflammation responses and an imbalance of airway nerve regulation. The aim of the present study was to determine which serum proteins are differentially expressed between children with or without asthma and to ascertain the potential roles that these differentially expressed proteins (DEPs) may play in the pathogenesis of childhood asthma. Methods Serum samples derived from four children with asthma and four children without asthma were collected. The DEPs were identified by using isobaric tags for relative and absolute quantitation (iTRAQ) combined with liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses. Using biological information technology, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Cluster of Orthologous Groups of Proteins (COG) databases and analyses, we determined the biological processes associated with these DEPs. Key protein glucose-6-phosphate dehydrogenase (G6PD) was verified by enzyme linked immunosorbent assay (ELISA). Results We found 46 DEPs in serum samples of children with asthma vs. children without asthma. Among these DEPs, 12 proteins were significantly (>1.5 fold change) upregulated and 34 proteins were downregulated. The results of GO analyses showed that the DEPs were mainly involved in binding, the immune system, or responding to stimuli or were part of a cellular anatomical entity. In the KEGG signaling pathway analysis, most of the downregulated DEPs were associated with cardiomyopathy, phagosomes, viral infections, and regulation of the actin cytoskeleton. The results of a COG analysis showed that the DEPs were primarily involved in signal transduction mechanisms and posttranslational modifications. These DEPs were associated with and may play important roles in the immune response, the inflammatory response, extracellular matrix degradation, and the nervous system. The downregulated of G6PD in the asthma group was confirmed using ELISA experiment. Conclusion After bioinformatics analyses, we found numerous DEPs that may play important roles in the pathogenesis of childhood asthma. Those proteins may be novel biomarkers of childhood asthma and may provide new clues for the early clinical diagnosis and treatment of childhood asthma.

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NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor

Cited by 18 publications

References 52 publications

Spatiotemporal processing of neural cell adhesion molecules 1 and 2 by BACE1 in vivo

Spatiotemporal processing of neural cell adhesion molecules 1 and 2 by BACE1 in vivo

A signature of tumor immune microenvironment genes associated with the prognosis of non‑small cell lung cancer

Differentially expressed serum proteins in children with or without asthma as determined using isobaric tags for relative and absolute quantitation proteomics

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