NCAM‐induced intracellular signaling revisited

Ditlevsen, Dorte Kornerup; Povlsen, Gro Klitgaard; Berezin, Vladimir; Bock, Elisabeth

doi:10.1002/jnr.21551

Cited by 141 publications

(112 citation statements)

References 107 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…Additional experiments suggested that a single O-glycan attached to a serine residue at the very N terminus of NCAM7 possesses the bulk of the polysialic acid on this protein. 3 With this in mind, replacing NGKG with alanines may have made this glycan more accessible to the polySTs and enhanced polysialylation. More importantly, the observation that replacing PSSP eliminated NCAM N-glycan polysialylation, although only reducing NCAM7 O-glycan polysialylation, suggests that this sequence may play a dual role in NCAM polysialylation.…”

Section: The Ggvpi and Ngkg Sequences Do Not Play Roles In Ncam7 O-glmentioning

confidence: 99%

Sequences at the Interface of the Fifth Immunoglobulin Domain and First Fibronectin Type III Repeat of the Neural Cell Adhesion Molecule Are Critical for Its Polysialylation

Thompson

Foley

Swartzentruber

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Polysialic acid is an anti-adhesive glycan that modifies a select group of mammalian proteins. The primary substrate of the polysialyltransferases (polySTs) is the neural cell adhesion molecule (NCAM). Polysialic acid negatively regulates cell adhesion, is required for proper brain development, and is expressed in specific areas of the adult brain where it promotes on-going cell migration and synaptic plasticity. In addition, we show that the polyST, ST8SiaIV/PST, specifically binds NCAM and that this binding requires the FN1 domain. Replacing the FN1 PSSP sequences and the acidic patch residues decreases NCAM-polyST binding, whereas replacing the GGVPI and NGKG sequences has no effect. The location of GGVPI and NGKG in loops that flank the Ig5-FN1 linker and the proximity of PSSP to this linker suggest that GGVPI and NGKG sequences may be critical for stabilizing the Ig5-FN1 linker, whereas PSSP may play a dual role maintaining the Ig5-FN1 interface and a polyST recognition site. The neural cell adhesion molecule (NCAM)2 is a member of the immunoglobulin superfamily of proteins (1). It engages in both heterophilic and homophilic interactions that allow cell-cell adhesion and signal transduction (for review, see Refs. 2 and 3). NCAM is also the primary substrate for the two polysialyltransferases (polySTs) ST8SiaIV/PST (PST) and ST8SiaII/STX (4 -8). These two enzymes are capable of attaching long chains of ␣2,8-linked sialic acid residues to Nlinked glycans in the fifth immunoglobin-like domain (Ig5) of NCAM (9). These long chains of negatively charged sialic acid attenuate the interactions of NCAM and other cell surface adhesion molecules (10,11,16), and this is critical in developing embryos and neonates for proper neuronal cell migration and differentiation and brain development (for review, see Refs. 12 and 13).Mice null for NCAM show mild defects such as a reduced olfactory bulb size, decreased mossy fiber fasciculation, and deficits in spatial learning (14). In contrast, mice lacking the two polySTs show severe defects in brain architecture, hydrocephaly, and most die within 4 weeks of birth (15). A triple knock-out of NCAM and the polySTs rescues the lethal phenotype, indicating that polysialic acid is needed to prevent early and inappropriate cell adhesion and differentiation (15). In mammals, polyST expression decreases soon after birth, and in the adult animal NCAM is mostly unpolysialylated except in a few specific areas of the brain that require on-going cell migration and synaptic plasticity, such as the hippocampus, hypothalamus, and olfactory bulb (13,(17)(18)(19)(20). In addition, polysialic acid is aberrantly expressed in several pediatric and adult cancers, such as neuroblastoma, small and nonsmall cell lung carcinoma, and Wilms' tumor (21-26). Polysialic acid re-expression in cancer cells has been suggested to increase tumor invasiveness and to promote tumor growth by down-regulating NCAM signaling that activates tumor suppression pathways (27).Polysialic acid is expressed on a very small subs...

show abstract

Section: The Ggvpi and Ngkg Sequences Do Not Play Roles In Ncam7 O-glmentioning

confidence: 99%

Sequences at the Interface of the Fifth Immunoglobulin Domain and First Fibronectin Type III Repeat of the Neural Cell Adhesion Molecule Are Critical for Its Polysialylation

Thompson

Foley

Swartzentruber

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Even though rising evidence supports a role for astrocytes in synaptic plasticity and potentially in learning (Schummers, Yu, & Sur, 2008), a putative role for NCAM-120 in such processes has not yet been explored. However, substantial evidence supports a role for NCAM-140 (expressed both in neurons and glia) in plasticity and intracellular signaling (for a review, see Ditlevsen, Povlsen, Berezin, & Bock, 2008). For example, a constitutive association has been found between NCAM-140 and Fyn (a member of the Src family of non-receptor tyrosine kinases highly expressed in neural tissue) (Ditlevsen et al, 2008).…”

Section: Stressful Learning As a Model Of Intrinsic Stress And Ncammentioning

confidence: 99%

“…However, substantial evidence supports a role for NCAM-140 (expressed both in neurons and glia) in plasticity and intracellular signaling (for a review, see Ditlevsen, Povlsen, Berezin, & Bock, 2008). For example, a constitutive association has been found between NCAM-140 and Fyn (a member of the Src family of non-receptor tyrosine kinases highly expressed in neural tissue) (Ditlevsen et al, 2008). Interestingly, Fyn activation leads to recruitment and activation of the focal adhesion kinase (FAK), which is another non-receptor tyrosine kinase.…”

Section: Stressful Learning As a Model Of Intrinsic Stress And Ncammentioning

confidence: 99%

Learning under stress: A role for the neural cell adhesion molecule NCAM

Bisaz

Conboy

Sandi

2009

Neurobiology of Learning and Memory

View full text Add to dashboard Cite

a b s t r a c tStress is known to be a potent modulator of brain function and cognition. While prolonged and/or excessive stress generally exerts negative effects on learning and memory processes, acute stress can have differential effects on memory function depending on a number of factors (such as stress duration, stress intensity, timing and the source of the stress, as well as the learning type under study). Here, we have focused on the effects of 'acute' stress, and examined the literature attending to whether the ''source of stress" is 'intrinsic' (i.e., when stress is originated by the cognitive task) or 'extrinsic' (i.e., when stress is induced by elements not related to the cognitive task). We have questioned here whether the neural cell adhesion molecule of the immunoglobulin superfamily (NCAM) contributes to the neurobiological mechanisms that translate the effects of these two different stress sources into the different behavioral and cognitive outcomes. NCAM is a cell adhesion macromolecule known to play a critical role in development and plasticity of the nervous system. NCAM and its post-translational modified form PSA-NCAM are critically involved in mechanisms of learning and memory and their expression levels are known to be highly susceptible to modulation by stress. Whereas available data are insufficient to conclude as to whether NCAM mediates extrinsic stress effects on learning and memory processes, we present systematic evidence supporting a key mediating role for both NCAM and PSA-NCAM in the facilitation of memory consolidation induced by intrinsic stress. Furthermore, NCAM is suggested to participate in some of the bidirectional effects of stress on memory processes, with its enhanced synaptic expression involved in facilitating stress actions while its reduced expression being related to impairing effects of stress on memory function.

show abstract

“…Since the PLA will only detect proteins in close proximity of each other the presence of signal indicates that NCAM and FGFR2 are co-localizing in the mouse oocyte membrane. NCAM may activate intracellular signaling pathways such as protein kinase A, protein kinase C (PKC) and the Ras-MAPK pathway (Ditlevsen et al, 2008). Although all three NCAM isoforms are redundant for embryo viability (Cremer et al, 1994) a secreted construct of the extracellular NCAM domain has been shown to result in embryonic lethality (Rabinowitz et al, 1996).…”

Section: Resultsmentioning

confidence: 99%

Co-localization of neural cell adhesion molecule and fibroblast growth factor receptor 2 in early embryo development

et al. 2011

View full text Add to dashboard Cite

During development there is a multitude of signaling events governing the assembly of the developing organism. Receptors for signaling molecules such as fibroblast growth factor receptor 2 (FGFR2) enable the embryo to communicate with the surrounding environment and activate downstream pathways. The neural cell adhesion molecule (NCAM) was first characterized as a cell adhesion molecule highly expressed in the nervous system, but recent studies have shown that it is also a signaling receptor. Using a novel single oocyte adaptation of the proximity ligation assay, we here show a close association between NCAM and FGFR2 in mouse oocytes and 2-cell embryos. Real-time PCR analyses revealed the presence of messenger RNA encoding key proteins in downstream signaling pathways in oocytes and early mouse embryos. In summary these findings show a co-localization of NCAM and FGFR2 in early vertebrate development with intracellular signaling pathways present to enable a cellular response. KEY WORDS: NCAM, FGFR2, mouse, PLA, developmentGrowth factors, such as fibroblast growth factors (FGFs) are crucial for the embryo development and the presence of FGF receptors in the developing oocyte have been shown in several vertebrate species (Ben-Haroush et al., 2005, Cailliau et al., 2003, Yoshida et al., 1998. There are four well-characterized FGF receptors (FGFRs 1-4), which contain a single transmembrane domain, an intracellular tyrosine kinase domain, and an extracellular FGF binding domain composed of two or three immunoglobulin (Ig)-like domains. The transcripts encoding FGF receptor 2 (FGFR2) are alternatively spliced to produce two FGFR2 transcripts (FGFR2-1 and FGFR2-2) that translate into two proteins with different carboxy-terminal halves of the Ig-III domain. This domain is determined by the inclusion of either exon IIIb (FGFR2-2) or exon IIIc (FGFR2-1), which controls ligandbinding specificity (Miki et al., 1992).Cell adhesion molecules (CAMs) are cell surface molecules responsible for mediating adhesion of cells to other cells and/or the extracellular matrix. The neural cell adhesion molecule (NCAM) is a member of the immunoglobulin superfamily and it is found in three major isoforms (Hinsby et al., 2004). The extracellular part of the NCAM consists of five Ig-like domains and two fibronectin Int.

show abstract

NCAM‐induced intracellular signaling revisited

Cited by 141 publications

References 107 publications

Sequences at the Interface of the Fifth Immunoglobulin Domain and First Fibronectin Type III Repeat of the Neural Cell Adhesion Molecule Are Critical for Its Polysialylation

Sequences at the Interface of the Fifth Immunoglobulin Domain and First Fibronectin Type III Repeat of the Neural Cell Adhesion Molecule Are Critical for Its Polysialylation

Learning under stress: A role for the neural cell adhesion molecule NCAM

Co-localization of neural cell adhesion molecule and fibroblast growth factor receptor 2 in early embryo development

Contact Info

Product

Resources

About