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PubMed2000

NCAM (neural cell adhesion molecules) expression in malignant mesotheliomas.

Neural cell adhesion molecules (NCAM) are adhesion molecules expressed by neural and neuroendocrine tumors and a few biphasic tumors such as synovialosarcomas and breast phyllode tumors. To investigate NCAM expression in mesotheliomas, we studied 26 cases of epithelioid (n = 12), biphasic (n = 11), and sarcomatoid (n = 3) malignant mesotheliomas (MM), in comparison with normal mesothelium, and 50 primary non-small cell lung carcinomas (NSCLC) (25 adenocarcinomas [ADC] and 25 squamous cell carcinomas [SCC]), using electron microscopy as a gold standard for recognition of MM. NCAM reactivity using 123C3 antibody was compared with that of NE markers such as chromogranin A and synaptophysin. Although normal mesothelium remains negative, NCAM was expressed in 19 of 26 MM (73%) with a membranous staining on frozen or paraffin sections. In 6 of 12 epithelioid MM, the tumor cells expressed NCAM, whereas in 5 cases stromal fibroblasts showed a strong but focal staining. In 11 biphasic MM, 4 presented an NCAM reactivity of both epithelioid and spindle cell components, whereas in 7, only fusiform component was NCAM positive. Two of 3 sarcomatoid MM showed an NCAM expression. Chromogranin expression was never seen, whereas synaptophysin was noticed in 2 cases. No case of NSCLC showed membranous 123C3 staining, whereas 2 ADC weakly expressed synaptophysin. We conclude that NCAM expression in MM is reminiscent of its expression in mesoderm during fetal life and consistent with that reported in other biphasic tumors. These data show that NCAM expression occurs in 73% of MM, highly exceeding that observed in lung cancer.

Adenocarcinoma↗
PubMed2005

Characterization of cDNA and the genomic sequence encoding canine neural-cell adhesion molecule, CD56/N-CAM.

The neural-cell adhesion molecule, CD56/N-CAM is a member of the immunoglobulin superfamily expressed by various tissues and cells, including natural killer (NK) cells. Despite the importance of CD56 as a marker for identifying NK cells in circulating blood, canine CD56 has not been identified. In the present study, we identified the canine counterparts of the 140-kDa (CD56-140) and 120-kDa (CD56-120) isoforms of human DC56. Both of amino acid sequences encoded by the canine CD56-140 and -120 cDNA showed high homology with those of human (both 96% homology), having well-conserved domains (five immunoglobulin, two fibronectin type III, and transmembrane and intracellular or glycosylphosphatidylinositol-linked domain) among various species (human, mouse, and feline). We revealed that the transcripts of canine CD56-140 and -120 arise from alternative mRNA splicing from a single gene located on canine chromosome 5. Moreover, the mRNA encoding canine CD56-140 was expressed at high levels constitutively by nervous system and endocrine tissues as has shown in other animals.

Alternative Splicing↗
PubMed1988

Neuroblastoma cell-oligodendrocyte interaction is mediated by neural cell adhesion molecules.

The role of neural cell adhesion molecule (NCAM) in the interaction between neurons and oligodendrocytes was studied using N2A neuroblastoma cells, which express only the 180,000 Mr NCAM and rat oligodendrocytes which express only 120,000 Mr NCAM. Oligodendrocytes bound to neuroblastoma cells, and the binding was inhibited by anti-NCAM, suggesting that NCAM is involved in oligodendrocyte-neuron interaction. The possible role of NCAM in myelination and remyelination is discussed.

Antigens, Surface↗
PubMed1993

Expression of highly polysialylated neural cell adhesion molecule in calcitonin-producing cells.

Calcitonin-producing cells are endocrine derivatives of the neural crest and have several neuron-like properties. Expression of the neural cell adhesion molecule in calcitonin-producing cells was examined using two types of antibodies to neural cell adhesion molecule: monoclonal antibody 12E3 recognizes the polysialic acid portion of highly polysialylated neural cell adhesion molecule, and monoclonal antibody AF11 and polyclonal antiserum react with the polypeptide portion common to three major isoforms of neural cell adhesion molecule. An immunohistochemical study revealed that highly polysialylated neural cell adhesion molecule was expressed both in fetal rat thyroidal calcitonin-producing cells and in a calcitonin-producing cell line, rMTC 6-23, established from explantable neoplasm of rat calcitonin-producing cells. The neural cell adhesion molecule in the rMTC 6-23 cells was further characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblot analysis. Two anti-neural cell adhesion molecule monoclonal antibodies, 12E3 and AF11, revealed a broad positive band around 200,000-250,000 mol. wt in solubilized proteins. When the polysialic acids were eliminated by neuraminidase treatment, the immunoreactivity to monoclonal antibody 12E3 was completely abolished, and core polypeptide corresponding to neural cell adhesion molecule with a molecular weight of 120,000 was detected by monoclonal antibody AF11. These results suggest that cells of the calcitonin-producing cell line express on their surfaces highly polysialylated 120,000 mol. wt form of neural cell adhesion molecule polypeptide.

Animals↗
PubMed1989

MUC18, a marker of tumor progression in human melanoma, shows sequence similarity to the neural cell adhesion molecules of the immunoglobulin superfamily.

The MUC18 antigen is an integral membrane glycoprotein of 113 kDa whose expression on primary human melanomas correlates with poor prognosis and the development of metastatic disease. MUC18 is expressed only sporadically in benign melanocytic nevi and thin primary melanomas that have a low probability of metastasizing. However, with increasing tumor thickness, MUC18 expression becomes more frequent and it is found on 80% of advanced primary tumors and metastases. MUC18-encoding cDNA clones were obtained by screening a human melanoma phage lambda expression library with monoclonal antibodies produced against the denatured antigen. The deduced sequence of 603 amino acids consists of a signal peptide, five immunoglobulin-like domains, a transmembrane region, and a short cytoplasmic tail. The highest sequence similarity is with a group of nervous system cell adhesion molecules, which includes neural cell adhesion molecule (N-CAM). The close structural relationship with these molecules suggests that MUC18 may also be a developmentally regulated cell adhesion molecule.

Amino Acid Sequence↗
PubMed2004

ShcA regulates neurite outgrowth stimulated by neural cell adhesion molecule but not by fibroblast growth factor 2: evidence for a distinct fibroblast growth factor receptor response to neural cell adhesion molecule activation.

Homophilic binding in trans of the neural cell adhesion molecule (NCAM) mediates adhesion between cells and leads, via activation of intracellular signaling cascades, to neurite outgrowth in primary neurons as well as in the neuronal cell line PC12. NCAM mediates neurite extension in PC12 cells by two principal routes of signaling: NCAM/Fyn and NCAM/fibroblast growth factor receptor (FGFR), respectively. Previous studies have shown that activation of mitogen-activated protein kinases is a pivotal point of convergence in NCAM signaling, but the mechanisms behind this activation are not clear. Here, we investigated the involvement of adaptor proteins in NCAM and fibroblast growth factor 2 (FGF2)-mediated neurite outgrowth in the PC12-E2 cell line. We found that both FGFR substrate-2 and Grb2 play important roles in NCAM as well as in FGF2-stimulated events. In contrast, the docking protein ShcA was pivotal to neurite outgrowth induced by NCAM, but not by FGF2, in PC12 cells. Moreover, in rat cerebellar granule neurons, phosphorylation of ShcA was stimulated by an NCAM mimicking peptide, but not by FGF2. This activation was blocked by inhibitors of both FGFR and Fyn, indicating that NCAM activates FGFR signaling in a manner distinct from FGF2 stimulation, and regulates ShcA phosphorylation by the concerted efforts of the NCAM/FGFR as well as the NCAM/Fyn signaling pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Regulation of neural cell adhesion molecule polysialylation state by cell-cell contact and protein kinase C delta.

Post-translational modification of neural cell adhesion molecule (NCAM) with alpha2,8-linked polysialic acid, which regulates homophilic adhesion and/or signal transduction events, is crucial to synaptic plasticity in the developing and adult brain. Evidence from in vitro models has implicated polysialylation in the regulation of cell growth, migration, and differentiation. Here, using two in vitro models, we demonstrate that polysialylation is downregulated by cell-cell contact and correlated with a state of neuronal differentiation. Furthermore, we report a role for protein kinase C delta (PKCdelta) in the regulation of NCAM polysialylation. Pharmacological studies using the PKC activator, phorbol myristate acetate, and inhibitors, calphostin-C, and staurosporine, demonstrated PKC activity to be inversely related to NCAM polysialylation in the mouse neuro-2A cell line. Isoform-specific immunoblot studies indicated this effect to be mediated by the calcium-independent PKCdelta isozyme, as its expression was inversely related to NCAM polysialylation state in both neuro-2A and rat PC-12 cell lines. Isoform specificity was further confirmed using the PKCdelta-selective inhibitor rottlerin, which produced a marked increase in PSA expression (36.9+/-5.25 a.u. vs. 24.7+/-0.80 arbitrary units control) coupled with a neuritogenic response. Likewise, decreased expression of PKCdelta was seen in nerve growth factor (NGF)-differentiated PC-12 cells. These findings suggest that the neuronal differentiation process may involve inhibition of PKCdelta, resulting in enhanced morphological plasticity, as evidenced by activation of NCAM polysialylation.

Acetophenones↗
PubMed1999

[Hippocampal adult neurogenesis and neuronal circuit formation: an analysis with special reference to polysialic acid-neural cell adhesion molecule].

It is generally thought that neurons are generated during the embryonic and early postnatal periods, but not in the adult. However, as neurogenesis continues in the dentate granule layer of the adult hippocampal formation, this would imply that new neuronal circuits are being added to the adult hippocampus by adult neurogenesis. Since these newly generated granule cells specifically express polysialic acid (PSA)-neural cell adhesion molecule (NCAM), it is possible to examine the new neuronal circuit formed by these cells using PSA immunohistochemisty. As for PSA function, it has been shown that the PSA expression of the mossy fibers is required for synaptic arrangement. Recently neurogenesis and PSA expression in the adult hippocampus are reported to be affected by neuronal activity and hormones, suggesting that they are closely associated with hippocampal plasticity.

Animals↗
PubMed2004

Overexpression of neural cell adhesion molecule in regenerative muscle fibers in 3-hydroxy-3-methylglutaryl coenzyme: A reductase inhibitor-induced rhabdomyolysis.

Skeletal muscle degeneration is a side effect of cholesterol-lowering hydroxymethylglutaryl coenzyme A reductase inhibitors. The expression of the cell-cell adhesion proteins, neural cell adhesion molecule and neural-cadherin was studied in a case of rhabdomyolysis induced by the hydroxymethylglutaryl coenzyme A reductase inhibitor cerivastatin. Neural cell adhesion molecule and N-cadherin participate in the interactions of muscle cells during skeletal myogenesis. In the adult muscle, neural cell adhesion molecule is restricted to neuromuscular sites but is re-expressed in denervated muscle and in rhabdomyolysis. Our results show expression of neural cell adhesion molecule in regenerative skeletal muscle fibers but not in degenerated or unaffected fibers in cerivastatin-induced rhabdomyolysis. In contrast, N-cadherin was not expressed. The presence of apoptotic cells was studied by a fluorescence-based Tdt-mediated dUTP nick-end labeling in the same sections. Apoptosis was detected in degenerative fibers and inflammatory cells but not in regenerative fibers. We hypothesize that the expression of neural cell adhesion molecule in regenerative fibers may have a protective role against apoptosis during rhabdomyolysis. Cerivastatin-induced rhabdomyolysis appears to have common features with rhabdomyolysis of other causes. The immunohistochemical study of neural cell adhesion molecule can serve as an additional tool in the evaluation of muscle regeneration in rhabdomyolysis.

Aged↗
PubMed1986

Nerve dependent regulation of neural cell adhesion molecule expression in skeletal muscle.

The expression of neural cell adhesion molecule was analysed by indirect immunofluorescence on adult mouse skeletal muscle subjected to a variety of experimental lesions. Adult mouse muscle does not express neural cell adhesion molecule at the sarcolemma. However, following denervation there is a rapid rise in neural cell adhesion molecule levels; this is initially in the cytoplasm of the myofibres but by 18 days there is intense reactivity at the sarcolemma. A nerve crush lesion was used to show that the increase in neural cell adhesion molecule levels following denervation is accompanied by a switch-off of neural cell adhesion molecule expression following reinnervation. Paralysis of skeletal muscle by botulinum toxin injection is sufficient to activate neural cell adhesion molecule expression. As paralysis of skeletal muscle by botulinum toxin is not accompanied by activation of muscle satellite cells or degeneration products of nerve or myelin, it suggests that the observed levels of neural cell adhesion molecule are synthesised by myofibres. As the expression of neural cell adhesion molecule in these lesions parallels the ability of skeletal muscle to accept innervation it is possible that neural cell adhesion molecule acts as a molecular cue at the sarcolemma in regulating synaptogenesis.

Animals↗
PubMed2005

Triple effect of mimetic peptides interfering with neural cell adhesion molecule homophilic cis interactions.

The neural cell adhesion molecule (NCAM) is pivotal in neural development, regeneration, and learning. Here we characterize two peptides, termed P1-B and P2, derived from the homophilic binding sites in the first two N-terminal immunoglobulin (Ig) modules of NCAM, with regard to their effects on neurite extension and adhesion. To evaluate how interference of these mimetic peptides with NCAM homophilic interactions in cis influences NCAM binding in trans, we employed a coculture system in which PC12-E2 cells were grown on monolayers of fibroblasts with or without NCAM expression and the rate of neurite outgrowth subsequently was analyzed. P2, but not P1-B, induced neurite outgrowth in the absence of NCAM binding in trans. When PC12-E2 cells were grown on monolayers of NCAM-expressing fibroblasts, the effect of both P1-B and P2 on neurite outgrowth was dependent on peptide concentrations. P1-B and P2 acted as conventional antagonists, agonists, and reverse agonists of NCAM at low, intermediate, and high peptide concentrations, respectively. The demonstrated in vitro triple pharmacological effect of mimetic peptides interfering with the NCAM homophilic cis binding will be valuable for the understanding of the actions of these mimetics in vivo.

Amino Acid Sequence↗
PubMed2000

Cellular signaling by neural cell adhesion molecules of the immunoglobulin superfamily.

Neural cell adhesion molecules (CAMs) of the immunoglobulin superfamily nucleate and maintain groups of cells at key sites during early development and in the adult. In addition to their adhesive properties, binding of CAMs can affect intracellular signaling. Their ability to influence developmental events, including cell migration, proliferation, and differentiation can therefore result both from their adhesive as well as their signaling properties. This review focuses on the two CAMs for which the most information is known, the neural CAM, N-CAM, and L1. N-CAM was the first CAM to be characterized and, therefore, has been studied extensively. The binding of N-CAM to cells leads to a number of signaling events, some of which result in changes in gene expression. Interest in L1 derives from the fact that mutations in its gene lead to human genetic diseases including mental retardation. Much is known about modifications of the L1 cytoplasmic domain and its interaction with cytoskeletal molecules. The study of CAM signaling mechanisms has been assay-dependent rather than molecule-dependent, with particular emphasis on assays of neurite outgrowth and gene expression, an emphasis that is maintained throughout the review. The signals generated following CAM binding that lead to alterations in cell morphology and gene expression have been linked directly in only a few cases. We also review information on other CAMs, giving special consideration to those that are anchored in the membrane by a phospholipid anchor. These proteins, including a form of N-CAM, are presumed to be localized in lipid rafts, membrane substructures that include distinctive subsets of cytoplasmic signaling molecules such as members of the src-family of nonreceptor protein tyrosine kinases. In the end, these studies may reveal that what CAMs do after they bind cells together may have as profound consequences for the cells as the adhesive interactions themselves. This area will therefore remain a rich ground for future studies.

Adult↗
PubMed1999

Expression and secretion of neural cell adhesion molecules by human pituitary adenomas.

Neural cell adhesion molecules (NCAMs) are found predominantly in neural, muscle and endocrine cells. Recent interest has focused on their potential role in tumorigenesis. We have analysed the expression and secretion of NCAM in a series of 48 human pituitary adenomas. Immunocytochemical analysis of 19 adenomas demonstrated NCAM expression in all tumours with, in each case, diffuse cytoplasmic staining being found with variable membrane accentuation. There were no apparent differences in the expression of immunoreactivity seen on sections between individual tumours. Cell culture media from 43 dispersed human pituitary tumours were analysed by immunoassay for the secretion of soluble NCAM and all the pituitary hormones. In contrast to the immunocytochemical studies, soluble NCAM was released from only 27% of human pituitary tumours, but this was not related to tumour type nor was the amount of soluble NCAM released correlated with the amount of pituitary hormone secreted by each adenoma. NCAM expression is common to all human pituitary adenoma types and the observed differences in release of soluble NCAM between individual tumours may reflect different molecular mechanisms, altering adhesive interactions between normal and adenomatous tissue.

Adenoma↗
PubMed2002

Differential effects of unnatural sialic acids on the polysialylation of the neural cell adhesion molecule and neuronal behavior.

In this study we have examined how unnatural sialic acids can alter polysialic acid expression and influence the adhesive properties of the neural cell adhesion molecule (NCAM). Unnatural sialic acids are generated by metabolic conversion of synthetic N-acyl mannosamines and are typically incorporated into cell-surface glycoconjugates. However, N-butanoylmannosamine and N-pentanoylmannosamine are effective inhibitors of polysialic acid (PSA) synthesis in stably transfected HeLa cells expressing NCAM and the polysialyltransferase STX. These cells were used as substrates to examine the effect of inhibiting PSA synthesis on the development of neurons derived from the chick dorsal root ganglion. N-butanoylmannosamine blocked polysialylation of NCAM and significantly reduced neurite outgrowth comparable with enzymatic removal of PSA by endoneuraminidases. As a result, neurite outgrowth was similar to that observed for non-polysialylated NCAM. In contrast, previous studies have shown that N-propanoyl sialic acid (SiaProp), generated from N-propanoylmannosamine, is readily accepted by polysialyltransferases and permits the extension of poly(SiaProp) on NCAM. Despite being immunologically distinct, poly(SiaProp) can promote neurite outgrowth similarly to natural polysialic acid. Thus, subtle structural differences in PSA resulting from the incorporation of SiaProp residues do not alter the antiadhesive properties of polysialylated NCAM.

Acetylation↗
PubMed2006

Metalloprotease-induced ectodomain shedding of neural cell adhesion molecule (NCAM).

Transmembrane forms of neural cell adhesion molecule (NCAM140, NCAM180(1)) are key regulators of neuronal development. The extracellular domain of NCAM can occur as a soluble protein in normal brain, and its levels are elevated in neuropsychiatric disorders, such as schizophrenia; however the mechanism of ectodomain release is obscure. Ectodomain shedding of NCAM140, releasing a fragment of 115 kD, was found to be induced in NCAM-transfected L-fibroblasts by the tyrosine phosphatase inhibitor pervanadate, but not phorbol esters. Pervanadate-induced shedding was mediated by a disintegrin metalloprotease (ADAM), regulated by ERK1/2 MAP kinase. In primary cortical neurons, NCAM was shed at high levels, and the metalloprotease inhibitor GM6001 significantly increased NCAM-dependent neurite branching and outgrowth. Moreover, NCAM-dependent neurite outgrowth and branching were inhibited in neurons isolated from a transgenic mouse model of NCAM shedding. These results suggest that regulated metalloprotease-induced ectodomain shedding of NCAM down-regulates neurite branching and neurite outgrowth. Thus, increased levels of soluble NCAM in schizophrenic brain have the potential to impair neuronal connectivity.

ADAM Proteins↗
PubMed1998

Neural cell adhesion molecule L1: relating disease to function.

Neural cell adhesion molecules of the immunoglobulin superfamily are important components of the network of guidance cues and receptors that govern axon growth and guidance during development. For neural cell adhesion molecule L1, the combined application of human genetics, knockout mouse technology, and cell biology is providing fundamental insight into the role of L1 in mediating neuronal differentiation. Disease-causing mutations as well as mouse models of L1 disruption can now be used to examine the relevance of L1 binding specificities and signal transduction pathways that have been observed in vitro.

Animals↗
PubMed1992

Neural cell adhesion molecule in aged mouse muscle.

Expression of the neural cell adhesion molecule was compared in endplate and non-endplate regions of skeletal muscles of mature and old CBF-1 mice, in order to determine whether age-related changes in neuromuscular morphology were correlated with age changes in neural cell adhesion molecule expression. Three muscles were examined: two (soleus and sternomastoid) showed age-related regionalization of nerve terminals as one manifestation of increased synaptic remodelling while the third (diaphragm) did not. Relative neural cell adhesion molecule content in these muscles was measured by densitometry of immunoblots after concentration by affinity chromatography. Expression of the major 140,000 mol. wt form of neural cell adhesion molecule, which was most abundant in the endplate region, was increased in sternomastoid and soleus of old compared to adult mouse, but was unchanged with age in diaphragm. A 70,000-80,000 mol. wt presumably proteolytic polypeptide fragment of neural cell adhesion molecule was increased in immunoblots of all old muscles. Immunocytochemical studies of skeletal muscles showed no difference in neural cell adhesion molecule cellular distribution in mature vs old mice, but in motor nerve of sternomastoid, the number of neural cell adhesion molecule-positive nerve fibers was increased in old mice. Several lines of evidence indicated that partial denervation was rare in old CBF-1 mice, and therefore could not account for the findings above. Selective increase of 140,000 mol. wt neural cell adhesion molecule expression in the junctional regions of those muscles of old mice which show neuromuscular remodelling indicates that this adhesion molecule may play a role in the age-related instability of motor nerve terminals.

Aging↗
PubMed2000

Mice deficient in the polysialyltransferase ST8SiaIV/PST-1 allow discrimination of the roles of neural cell adhesion molecule protein and polysialic acid in neural development and synaptic plasticity.

Functional properties of the neural cell adhesion molecule (NCAM) are strongly influenced by polysialylation. We used gene-targeting to generate mice lacking ST8SiaIV/PST-1, one of the polysialyltransferases responsible for addition of polysialic acid (PSA) to NCAM. Mice homozygous for the null mutation reveal normal development of gross anatomical features. In contrast to NCAM-deficient mice, olfactory precursor cells in the rostral migratory stream express PSA and follow their normal pathway. Furthermore, delamination of mossy fibers in the hippocampal CA3 region, as found in NCAM-deficient mice, does not occur in ST8SiaIV mutants. However, during postnatal development these animals show a decrease of PSA in most brain regions compared to wild-type animals. Loss of PSA in the presence of NCAM protein but in the absence of obvious histological changes allowed us to directly address the role of PSA in synaptic plasticity. Schaffer collateral-CA1 synapses, which express PSA in wild types, showed impaired long-term potentiation (LTP) and long-term depression (LTD) in adult mutants. This impairment was age-dependent, following the time course of developmental disappearance of PSA. Contrary to NCAM mutant mice, LTP in ST8SiaIV mutants was undisturbed at mossy fiber-CA3 synapses, which do not express PSA in wild-type mice. The results demonstrate an essential role for ST8SiaIV in synaptic plasticity in hippocampal CA1 synapses, whereas PSA produced by different polysialyltransferase or polysialyltransferases at early stages of differentiation regulates migration of neural precursor cells and correct lamination of mossy fibers. We suggest that NCAM but not PSA is likely to be important for LTP in the hippocampal CA3 region.

Aging↗