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Direct evidence that Neural Cell Adhesion Molecule (NCAM) polysialylation increases intermembrane repulsion and abrogates adhesion

Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Journal of Biological Chemistry (Impact Factor: 4.6). 02/2005; 280(1):137-45. DOI: 10.1074/jbc.M410216200
Source: PubMed

ABSTRACT Molecular force measurements quantified the impact of polysialylation on the adhesive properties both of membrane-bound neural cell adhesion molecule (NCAM) and of other proteins on the same membrane. These results show quantitatively that NCAM polysialylation increases the range and magnitude of intermembrane repulsion. The repulsion is sufficient to overwhelm both homophilic NCAM and cadherin attraction at physiological ionic strength, and it abrogates the protein-mediated intermembrane adhesion. The steric repulsion is ionic strength dependent and decreases substantially at high monovalent salt concentrations with a concomitant increase in the intermembrane attraction. The magnitude of the repulsion also depends on the amount of polysialic acid (PSA) on the membranes, and the PSA-dependent attenuation of cadherin adhesion increases with increasing PSA-NCAM:cadherin ratios. These findings agree qualitatively with independent reports based on cell adhesion studies and reveal the likely molecular mechanism by which NCAM polysialylation regulates cell adhesion and intermembrane space.

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Available from: Deborah E Leckband, Jul 27, 2015
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    • "Polysialic acid (PSA), an a2,8-linked polymer of sialic acid, was discovered for the first time by Jukka Finne in a developing brain [11]. Negative charges which surround PSA polymers absorb more water molecules near the outer cell membrane which leads to repulsion and increasing distances between cells during cell migration in the developing CNS [12]. Polysialylation is the product of two isozymes; ST8SIA2 (STX), predominantly expressed during embryonic life, and ST8SIA4 (PST), responsible for polysialilation of NCAM in adults rat brain [13]. "
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    ABSTRACT: During embryonic life a group of cells become proliferated, migrated and differentiated to develop central nervous system. Migration has been suggested to be due to accumulation of polysialic acid (PSA), a negatively-charged glycoside, on the outer cell membrane. The same event happens to PSA in a tumor mass as well. Polysialylation is the product of polysialyl transfrase isozymes; STX (ST8SIA2), the embryonic active isoform, and PST (ST8SIA4), expressed in adults CNS. Additionally, cAMP concludes to activation of PKA and EPAC resulting to the initiation of gene expressions which are highly required during development. EPAC, the latter known target of cAMP in mammalian nervous system, has proliferative properties in the developing CNS. We propose for the proper action of EPAC, namely CNS development, the presence of STX and its elevation after EPAC activation is mandatory. This hypothesis is put forward after observing, in a preliminary experiment, a relationship between EPAC activation and STX mRNA expression levels in rat hippocampus. The interaction between EPAC and STX may be suggested to be through EPAC-induced gene expression of the latter. From the above assumptions one may suggest the use of EPAC activators as neurogenesis inducers and its inhibitors as tumor modulators.
    Medical Hypotheses 05/2013; 81(2). DOI:10.1016/j.mehy.2013.04.047 · 1.07 Impact Factor
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    • "We therefore asked whether PSA affected the molecular mobility of NCAM locally within cell membrane microdomains in isolated cells. Indeed, this could also be a reflection of increased molecular repulsion between adjacent proteins in the same membrane, as suggested by Johnson et al. (2005). By using FRAP and FCS to study NCAM dynamics, we brought the evidence that PSA increased the mobility of NCAM itself at the cell membrane without effect on its trafficking or confinement in small domains. "
    Chemical Biology, 02/2012; , ISBN: 978-953-51-0049-2
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    • "It is highly up-regulated in the nervous system during the embryonic development of mammals and fishes and drastically downregulated post-natally or around hatching, respectively (Rutishauser 2008; Gascon et al. 2010; Hildebrandt et al. 2010; Kleene and Schachner 2010). Due to its large volume, polySia inhibits NCAM1 homophilic binding; it thereby increases intermembrane repulsion and abrogates cell adhesion (Johnson et al. 2005). In addition, it affects other NCAM1-dependent cell surface interactions in several ways (reviewed by Hildebrandt et al. 2007). "
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    ABSTRACT: Polysialic acid (polySia) is mainly described as a glycan modification of the neural cell adhesion molecule NCAM1. PolySia-NCAM1 has multiple functions during the development of vertebrate nervous systems including axon extension and fasciculation. Phylogenetic analyses reveal the presence of two related gene clusters, NCAM1 and NCAM2, in tetrapods and fishes. Within the ncam1 cluster, teleost fishes express ncam1a (ncam) and ncam1b (pcam) as duplicated paralogs which arose from a second round of ray-finned fish-specific genome duplication. Tetrapods, in contrast, express a single NCAM1 gene. Using the zebrafish model, we identify Ncam1b as a novel major carrier of polySia in the nervous system. PolySia-Ncam1a is expressed predominantly in rostral regions of the developing nervous system, whereas polySia-Ncam1b prevails caudally. We show that ncam1a and ncam1b have different expression domains which only partially overlap. Furthermore, Ncam1a and Ncam1b and their polySia modifications serve different functions in axon guidance. Formation of the posterior commissure at the forebrain/midbrain junction requires polySia-Ncam1a on the axons for proper fasciculation, whereas Ncam1b, expressed by midbrain cell bodies, serves as an instructive guidance cue for the dorso-medially directed growth of axons. Spinal motor axons, on the other hand, depend on axonally expressed Ncam1b for correct growth toward their target region. Collectively, these findings suggest that the genome duplication in the teleost lineage has provided the basis for a functional diversification of polySia carriers in the nervous system.
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