Structural Basis for a Direct Interaction between FGFR1 and NCAM and Evidence for a Regulatory Role of ATP

Kiselyov, Vladislav V.; Skladchikova, Galina; Hinsby, Anders M.; Jensen, Peter Holme; Kulahin, Nikolaj; Soroka, Vladislav; Pedersen, Nina Marie; Tsetlin, Victor I.; Poulsen, Flemming M.; Berezin, Vladimir; Bock, Elisabeth

doi:10.1016/s0969-2126(03)00096-0

Cited by 243 publications

(359 citation statements)

References 27 publications

(3 reference statements)

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“…1). For example, NCAM interacts with the fibroblast growth factor receptor (FGFR), promoting signaling events that lead to neurite outgrowth (51,52). In non-neuronal cells, the binding of soluble NCAM to FGFR1 has been shown to induce receptor internalization and recycling, thereby prolonging signaling and promoting cell migration (53).…”

Section: Discussionmentioning

confidence: 99%

Sequences from the First Fibronectin Type III Repeat of the Neural Cell Adhesion Molecule Allow O-Glycan Polysialylation of an Adhesion Molecule Chimera

Foley

Swartzentruber

Thompson

et al. 2010

Journal of Biological Chemistry

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Polysialic acid is a developmentally regulated, anti-adhesive polymer that is added to N-glycans on the fifth immunoglobulin domain (Ig5) of the neural cell adhesion molecule (NCAM). We found that the first fibronectin type III repeat (FN1) of NCAM is required for the polysialylation of N-glycans on the adjacent Ig5 domain, and we proposed that the polysialyltransferases recognize specific sequences in FN1 to position themselves for Ig5 N-glycan polysialylation. Other studies identified a novel FN1 acidic surface patch and ␣-helix that play roles in NCAM polysialylation. Here, we characterize the contribution of two additional FN1 sequences, Pro The neural cell adhesion molecule (NCAM)2 is a member of the immunoglobulin superfamily. It is expressed on the cell surface where it engages in homophilic and heterophilic interactions, resulting in cell adhesion and modulation of signal transduction cascades (reviewed in Refs. 1, 2). In the developing embryo and neonate, NCAM is modified by the addition of long chains of ␣2,8-polysialic acid (3, 4). The presence of this highly hydrated and negatively charged carbohydrate polymer disrupts overall cell adhesion and allows cell migration (5-7). Polysialylation is catalyzed by the polysialyltransferases (polySTs), . NCAM polysialylation is critical during embryogenesis and early postnatal development. Mice that are null for both polySTs are born at Mendelian ratios but have severe neuronal defects, fail to thrive, and the majority die within 4 weeks of birth (12). Simultaneous deletion of NCAM and the polySTs rescues the lethal phenotype, indicating that polysialic acid is required to down-regulate the adhesive properties of NCAM during development (12). In addition, using varying allelic combinations of ST8SiaIV, ST8SiaII, and NCAM, Hildebrandt et al. (13) demonstrated that an aberrant increase in the level of unpolysialylated NCAM caused defects in brain connectivity in postnatal day 1 mice.NCAM is mainly unpolysialylated in the adult brain (3, 4). However, polysialylated NCAM does persist in specific regions of the central nervous system, including the olfactory bulb and hippocampus, where it functions in cell migration, synaptic plasticity, and repair (14 -17). Highly polysialylated NCAM is also re-expressed in several cancers, including neuroblastoma, glioma, small cell and non-small cell lung tumors, and Wilms' tumor, where it has been suggested to promote cancer invasiveness (18 -23). Recently, polysialylated NCAM has been shown to enhance metastasis of a murine model of lung cancer (24) and has been implicated in colorectal carcinoma progression (25). In addition, polysialic acid has been demonstrated to be involved in hematopoietic development (26,27). For example, ST8SiaIV Ϫ/Ϫ mice have reduced thymocyte numbers due to fewer progenitor cells mobilizing to the thymus (27).Although NCAM is by far the most abundant and well documented polysialylated protein, it is striking that only six other polysialylated glycoproteins have been identified. These are the ␣ subu...

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Section: Discussionmentioning

confidence: 99%

Sequences from the First Fibronectin Type III Repeat of the Neural Cell Adhesion Molecule Allow O-Glycan Polysialylation of an Adhesion Molecule Chimera

Foley

Swartzentruber

Thompson

et al. 2010

Journal of Biological Chemistry

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“…To address this possibility, we deleted the membrane proximal FnIII domain from the N-CAM-Fc fusion protein (⌬Fn2, Fig. 1A), FnIII and Ig domains are similar in size (19,30), and compared the ability of ⌬Fn2 to mediate bead aggregation with that of the wild-type protein. In this assay the ⌬Fn2 was as effective as the entire extracellular region in mediating aggregation (Fig.…”

Section: Fig 7 N-cam-transfected L Cell Aggregation Is Insensitive Tomentioning

confidence: 99%

Neural Cell Adhesion Molecule (N-CAM) Homophilic Binding Mediated by the Two N-terminal Ig Domains Is Influenced by Intramolecular Domain-Domain Interactions

Atkins¹,

Gallin

Owens

et al. 2004

Journal of Biological Chemistry

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“…Structural evidence suggests that NCAM molecules form cis dimers in the cell membrane and these cis dimers mediate trans interactions between cells via formation of two-dimensional zippers [12,13]. In neurons the extracellular part of NCAM has been shown to bind and mediate phosphorylation/activation of the fibroblast growth factor receptor (FGFR) [14,15]. This initiates signalling downstream FGFR leading to activation of PKC and an increase in the intracellular concentrations of arachidonic acid and Ca 2+ [16].…”

Section: Introductionmentioning

confidence: 99%

IL-1β-induced pro-apoptotic signalling is facilitated by NCAM/FGF receptor signalling and inhibited by the C3d ligand in the INS-1E rat beta cell line

et al. 2006

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Aims/hypothesis: IL-1β released from immune cells induces beta cell pro-apoptotic signalling via mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB). In neurons, the neural cell adhesion molecule (NCAM) signals to several elements involved in IL-1β-induced pro-apoptotic signalling in beta cells. Pancreatic beta cells express NCAM, but its biological effects in these cells are unclear. The aim of this study was to investigate whether there is cross-talk between NCAM signalling and cytokine-induced pro-apoptotic signalling. Materials and methods: Western blotting was used to investigate levels of NCAM and inducible nitric oxide synthase, phosphorylation of Src and MAPKs, and cleavage of caspase-3. MAPK activity was investigated with an in vitro kinase assay. Apoptosis was detected by cleaved caspase-3 and a Cell Death Detection ELISA plus assay. NCAM-induced fibroblast growth factor receptor (FGFR) activation was investigated in NCAM −/− Trex293 cells where FGFR phosphorylation was measured by Western blotting after NCAM transfection. Results: Preexposure of INS-1E cells to the FGFR-inhibitor SU5402, but not to the Src-inhibitor PP2, dose-dependently inhibited IL-1β-mediated MAPK activity. A synthetic peptide, C3d, reported to bind NCAM, did not activate MAPK or Akt as reported in neurons but inhibited IL-1β-induced MAPK activity, thereby mimicking the effect of SU5402. Furthermore, C3d inhibited NCAM-induced FGFR phosphorylation and apoptosis induced by IL-1β plus IFN-γ, but did not affect IL-1β-induced NF-κB signalling. Conclusions/interpretation: We suggest that NCAM signalling through FGFR is required for efficient IL-1β pro-apoptotic signalling by facilitating IL-1β-induced MAPK activation downstream of the NF-κB-MAPK branching point. Further, these data identify a novel function of C3d as an inhibitor of NCAM-induced FGFR activity and of IL-1β-induced MAPK activation in beta cells.

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Structural Basis for a Direct Interaction between FGFR1 and NCAM and Evidence for a Regulatory Role of ATP

Cited by 243 publications

References 27 publications

Sequences from the First Fibronectin Type III Repeat of the Neural Cell Adhesion Molecule Allow O-Glycan Polysialylation of an Adhesion Molecule Chimera

Sequences from the First Fibronectin Type III Repeat of the Neural Cell Adhesion Molecule Allow O-Glycan Polysialylation of an Adhesion Molecule Chimera

Neural Cell Adhesion Molecule (N-CAM) Homophilic Binding Mediated by the Two N-terminal Ig Domains Is Influenced by Intramolecular Domain-Domain Interactions

IL-1β-induced pro-apoptotic signalling is facilitated by NCAM/FGF receptor signalling and inhibited by the C3d ligand in the INS-1E rat beta cell line

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