Signaling mechanisms of neurite outgrowth induced by the cell adhesion molecules NCAM and N-Cadherin

Hansen, Steen; Berezin, Vladimir; Bock, Elisabeth

doi:10.1007/s00018-008-8290-0

Cited by 107 publications

(118 citation statements)

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“…Variable roles of JLP and N-cadherin according to the differential cellular context have been demonstrated in previous studies. For example, JLP has been reported to negatively regulate NGFinduced neurite outgrowth via JNK inhibition during neuronal differentiation (36) as opposed to the previous report demonstrating that N-cadherin is involved in NGF-induced neurite outgrowth (37). Thus, the association between N-cadherin and JLP may be involved in differential cell fate by modulating signaling pathways including p38 MAPK and JNK according to the cellular context.…”

Section: Discussionmentioning

confidence: 85%

N-cadherin Regulates p38 MAPK Signaling via Association with JNK-associated Leucine Zipper Protein

Andō

Uemura

Kuzuya

et al. 2011

Journal of Biological Chemistry

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Synaptic loss, which strongly correlates with the decline of cognitive function, is one of the pathological hallmarks of Alzheimer disease. N-cadherin is a cell adhesion molecule essential for synaptic contact and is involved in the intracellular signaling pathway at the synapse. Here we report that the functional disruption of N-cadherin-mediated cell contact activated p38 MAPK in murine primary neurons, followed by neuronal death. We further observed that treatment with A␤ 42 decreased cellular N-cadherin expression through NMDA receptors accompanied by increased phosphorylation of both p38 MAPK and Tau in murine primary neurons. Moreover, expression levels of phosphorylated p38 MAPK were negatively correlated with that of N-cadherin in human brains. Proteomic analysis of human brains identified a novel interaction between N-cadherin and JNK-associated leucine zipper protein (JLP), a scaffolding protein involved in the p38 MAPK signaling pathway. We demonstrated that N-cadherin expression had an inhibitory effect on JLP-mediated p38 MAPK signal activation by decreasing the interaction between JLP and p38 MAPK in COS7 cells. Also, this study demonstrated a novel physical and functional association between N-cadherin and p38 MAPK and suggested neuroprotective roles of cadherinbased synaptic contact. The dissociation of N-cadherin-mediated synaptic contact by A␤ may underlie the pathological basis of neurodegeneration such as neuronal death, synaptic loss, and Tau phosphorylation in Alzheimer disease brain.Alzheimer disease (AD) 2 is pathologically characterized by the presence of amyloid ␤-peptide (A␤) and neurofibrillary tangles in the neocortex and hippocampus. Insoluble A␤ fibrillar aggregates found in senile plaques have long been considered to cause the neurodegeneration of AD. On the other hand, synaptic loss is another pathological hallmark of AD, which strongly correlates with the severity of cognitive impairment better than senile plaques or neurofibrillary tangles (1). Interestingly, recent studies from AD mouse models have shown that learning impairment and synaptic dysfunction become apparent before the formation of plaques, suggesting the hypothesis that soluble A␤ causes "synaptic failure" before plaques develop and neuron death occurs (2). Converging lines of evidence suggest that natural soluble A␤ oligomers trigger synaptic loss (3). Thus, in addition to the investigation of molecular mechanisms, which develop senile plaques and neurofibrillary tangles, research focusing on synaptic dysfunction is important to clarify the earliest pathology in AD.Presenilin (PS) 1/2 is the essential catalytic component of ␥-secretase proteolytic complex (4, 5), which is responsible for the final cleavage of amyloid precursor protein to generate A␤ peptides. Mutations in PS1 have been known as the most common cause of autosomal dominant familial Alzheimer disease (6 -8). Interestingly, PS1 binds to N-cadherin, which is an essential molecule for synaptic contact and is abundantly localized in hippocampal synapses ...

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Section: Discussionmentioning

confidence: 85%

N-cadherin Regulates p38 MAPK Signaling via Association with JNK-associated Leucine Zipper Protein

Andō

Uemura

Kuzuya

et al. 2011

Journal of Biological Chemistry

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“…ECM remodeling and changes in cellular interactions with the ECM are important for the initiation of EMT (35). Integrin complexes enable cells to receive signals from ECM proteins through interaction with signal mediators, including integrin-linked kinase (ILK) and parvin (41,43). Following treatment of U87 cells with TGF-β1 for 72 h, there was a slight increase in ILK expression (1.2-fold) and no detectable change in parvin-α levels, whereas the protein level of parvin-β was decreased (0.66-fold).…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of the effect of TGF-β1 on U87 human glioblastoma cells

Bryukhovetskiy

Шевченко

2016

Oncology Letters

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Abstract. Glioblastoma multiforme (GBM) is the most widespread and aggressive type of primary brain tumor. The prognosis following diagnosis with GBM is poor, with a median survival time of 14 months. Tumor cell invasion, metastasis and proliferation are the major causes of mortality in patients with GBM. In order to develop effective GBM treatment methods it is necessary to identify novel targets involved in these processes. Recently, there has been increasing interest in investigating the signaling pathways involved in GBM development, and the transforming growth factor-β (TGF-β) signaling pathway is understood to be significant for regulating the behavior of GBM, as well as stimulating its invasion and metastatic development. Particular interest has been given to investigating the modulation of TGF-β-induced epithelial-to-mesenchymal transition (EMT); during this process, epithelial cells transdifferentiate into mobile cells with a mesenchymal phenotype. The induction of EMT increases the invasiveness of various types of carcinoma; however, the role of TGF-β in this process remains to be elucidated, particularly in the case of GBM. The current study presents a comparative proteome mapping of the U87 human glioblastoma cell line, with and without TGF-β1 treatment. Proteome analysis identified numerous proteins involved in the molecular mechanisms of GBM oncogenesis and TGF-β1 signaling in glioblastoma. The results of the present study facilitated the identification of novel potential markers of metastasis and candidates for targeted glioblastoma therapy, which may potentially be validated and used in clinical medicine to develop improved approaches for GBM diagnosis and treatment.

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“…These events have not been thoroughly characterized but are hypothesized to occur both via direct activation of downstream signaling cascades and via interactions with other cell surface receptors such as FGFRs (Hansen et al, 2008a). In an in vitro study by Christensen et al, (2006) using recombinant NCAM (F3 module 1-2) and FGFR2 (Ig module 2-3) proteins it was shown that the binding between the recombinant proteins had Kd values similar to that of NCAM-FGFR1 binding indicating that NCAM might activate FGFR2 in a similar manner as it activates FGFR1.…”

Section: Resultsmentioning

confidence: 99%

“…5B). It has been speculated that NCAM participates in FGFR-induced signaling by binding to PLC, thereby bringing FGFR and PLC into close proximity of each other (Hansen et al, 2008a). However, a direct interaction between NCAM and FGFR1 was demonstrated only recently by surface plasmon resonance and nuclear magnetic resonance (Hansen et al, 2008b, Kiselyov et al, 2003.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2011

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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.

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Signaling mechanisms of neurite outgrowth induced by the cell adhesion molecules NCAM and N-Cadherin

Cited by 107 publications

References 104 publications

N-cadherin Regulates p38 MAPK Signaling via Association with JNK-associated Leucine Zipper Protein

N-cadherin Regulates p38 MAPK Signaling via Association with JNK-associated Leucine Zipper Protein

Molecular mechanisms of the effect of TGF-β1 on U87 human glioblastoma cells

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

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