A short segment within the cytoplasmic domain of the neural cell adhesion molecule (N-CAM) is essential for N-CAM-induced NF-κB activity in astrocytes

Little, Edward B.; Crossin, Kathryn L.; Krushel, Leslie A.; Edelman, Gerald M.; Cunningham, Bruce A.

doi:10.1073/pnas.041597098

Cited by 18 publications

(10 citation statements)

References 48 publications

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“…It has long been known that NCAM1 can be phosphorylated within its intracellular domain by casein kinase 1 (CK1) and GSK3 but in these early studies the phospho-acceptor site was not determined35. Subsequent attempts to map the NCAM1 phosphorylation sites highlighted initially a domain in juxtaposition to the inner face of the plasma membrane but also a putative serine 761 phospho-acceptor site that conforms to the GSK3 consensus motif36. The design of the latter phospho-site mapping experiments precluded the detection of phosphorylation sites observed in this study.…”

Section: Discussionmentioning

confidence: 99%

A ZIP6-ZIP10 heteromer controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-to-mesenchymal transition

Dylan

Mehrabian

Williams

et al. 2017

Sci Rep

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The prion protein (PrP) evolved from the subbranch of ZIP metal ion transporters comprising ZIPs 5, 6 and 10, raising the prospect that the study of these ZIPs may reveal insights relevant for understanding the function of PrP. Building on data which suggested PrP and ZIP6 are critical during epithelial-to-mesenchymal transition (EMT), we investigated ZIP6 in an EMT paradigm using ZIP6 knockout cells, mass spectrometry and bioinformatic methods. Reminiscent of PrP, ZIP6 levels are five-fold upregulated during EMT and the protein forms a complex with NCAM1. ZIP6 also interacts with ZIP10 and the two ZIP transporters exhibit interdependency during their expression. ZIP6 contributes to the integration of NCAM1 in focal adhesion complexes but, unlike cells lacking PrP, ZIP6 deficiency does not abolish polysialylation of NCAM1. Instead, ZIP6 mediates phosphorylation of NCAM1 on a cluster of cytosolic acceptor sites. Substrate consensus motif features and in vitro phosphorylation data point toward GSK3 as the kinase responsible, and interface mapping experiments identified histidine-rich cytoplasmic loops within the ZIP6/ZIP10 heteromer as a novel scaffold for GSK3 binding. Our data suggests that PrP and ZIP6 inherited the ability to interact with NCAM1 from their common ZIP ancestors but have since diverged to control distinct posttranslational modifications of NCAM1.

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Section: Discussionmentioning

confidence: 99%

A ZIP6-ZIP10 heteromer controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-to-mesenchymal transition

Dylan

Mehrabian

Williams

et al. 2017

Sci Rep

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“…Finally, activation of most of the above mentioned pathways may result in activation of a number of different transcription factors and c-FOS, nuclear factor kB (NF-kB) and cyclic AMP response element-binding protein (CREB), are thought to be involved in NCAM mediated neurite outgrowth. Thus, NCAM stimulation results in increased expression of c-FOS [37] and activation of NF-kB [38,39] and CREB [40].…”

Section: Ncam-mediated Adhesion and Its Role In Neurite Outgrowthmentioning

confidence: 93%

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

Hansen

Berezin

Bock

2008

Cell. Mol. Life Sci.

107

115

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Formation of appropriate neural circuits depends on a complex interplay between extracellular guiding cues and intracellular signaling events that result in alterations of cytoskeletal dynamics and a neurite growth response. Surface-expressed cell adhesion molecules (CAMs) interact with the surroundings via the extracellular domain and bind to the cytoskeleton via their intracellular domain. In addition, several CAMs induce signaling events via direct interactions with intracellular proteins or via interactions with cell surface receptors. Thus, CAMs are obvious candidates for transmitting extracellular guidance cues to intracellular events and thereby regulating neurite outgrowth. In this review, we focus on two CAMs, the neural cell adhesion molecule (NCAM) and N-cadherin, and their ability to mediate signaling associated with a neurite outgrowth response. In particular, we will focus on direct interaction between NCAM and N-cadherin with a number of intracellular partners, as well as on their interaction with the fibroblast growth factor receptor (FGFR).

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“…Transmembrane isoforms of NCAM can also be phosphorylated at serine and threonine residues located in the intracellular part of the molecule (41)(42)(43)(44), but reports of the importance of these phosphorylations are scant. However, three threonine residues (T788, T794 and T797 of rat NCAM) have been shown to be of importance for NCAM-mediated activation of the transcription factor NF-jB, and at least one of these (T794) is believed to be phosphorylated (45). The identified threonine residues lie within the section of NCAM encoded by exon 17, and are therefore present in all transmembrane isoforms of the protein.…”

Section: Posttranslational Modifications Of Ncammentioning

confidence: 98%

Zippers Make Signals: NCAM-mediated Molecular Interactions and Signal Transduction

et al. 2004

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The neural cell adhesion molecule, NCAM, is involved in multiple cis- and trans-homophilic interactions (NCAM binding to NCAM) thereby facilitating cell-cell adhesion through the formation of zipper-like NCAM-complexes. NCAM is also involved in heterophilic interactions with a number of proteins and extracellular matrix molecules. Some of these heterophilic interactions are mutually exclusive, and some interfere with or are dependent on homophilic NCAM interactions. Furthermore, both homo- and heterophilic interactions are modulated by posttranslational modifications of NCAM. Heterophilic NCAM-interactions initiate several intracellular signal transduction pathways ultimately leading to biological responses involving cellular differentiation, proliferation, migration and survival. Both homo- and heterophilic NCAM-interactions can be mimicked by synthetic peptides, which can induce NCAM-like signalling, and in vitro and in vivo studies suggest that such NCAM mimetics may be used for the treatment of neurodegenerative disorders.

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A short segment within the cytoplasmic domain of the neural cell adhesion molecule (N-CAM) is essential for N-CAM-induced NF-κB activity in astrocytes

Cited by 18 publications

References 48 publications

A ZIP6-ZIP10 heteromer controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-to-mesenchymal transition

A ZIP6-ZIP10 heteromer controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-to-mesenchymal transition

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

Zippers Make Signals: NCAM-mediated Molecular Interactions and Signal Transduction

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