The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking

Francavilla, Chiara; Cattaneo, Paola; Berezin, Vladimir; Bock, Elisabeth; Ami, Diletta; Marco, Ario de; Christofori, Gerhard; Cavallaro, Ugo

doi:10.1083/jcb.200903030

Cited by 113 publications

(154 citation statements)

References 69 publications

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“…In addition expression of many other chemokine receptors (CCR1, CCR4, CCR6, CCR7, CXCR3, CXCR6; data not shown), chemokine ligands (CXCL1, CXCL6, CXCL9) (Fig. 6A, B), and adhesion molecules [NCAM-1 (12,26,33), VCAM-1 (13), and ICAM] (Fig. 6A, B) known to be important for NSC chemotaxis and migration were also increased after BDNF treatment.…”

Section: Discussionmentioning

confidence: 99%

BDNF Pretreatment of Human Embryonic-Derived Neural Stem Cells Improves Cell Survival and Functional Recovery after Transplantation in Hypoxic–Ischemic Stroke

et al. 2015

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Intra-arterial neural stem cell (NSC) therapy has the potential to improve long-term outcomes after stroke. Here we evaluate if pretreatment of NSCs with brain-derived neurotrophic factor (BDNF) prior to transplantation improves cell engraftment and functional recovery following hypoxic-ischemic (HI) stroke. Human embryonicderived NSCs with or without BDNF pretreatment (1 h, 100 ng/ml) were transplanted 3 days after HI stroke. Functional recovery was assessed using the horizontal ladder test. Cell engraftment was evaluated using bioluminescence imaging (BLI) and histological counts of SC121 + cells. Fluoro-Jade C (FJC) and NeuN stains were used to evaluate neuroprotection. The effect of BDNF on NSCs was analyzed using a migration assay, immunocytochemistry, Luminex proteomic assay, and RT-qPCR.BLI analysis demonstrated significantly higher photon flux in the BDNF-treated NSC group compared to untreated NSC (p = 0.049) and control groups (p = 0.0021) at 1 week after transplantation. Immunohistochemistry confirmed increased transplanted cell survival in the cortex (p = 0.0126) and hippocampus (p = 0.0098) of animals injected with BDNF-treated NSCs compared to untreated NSCs. Behavioral testing revealed that the BDNF-treated NSC group demonstrated increased sensorimotor recovery compared to the untreated NSC and control groups (p < 0.001) over the 1-month period (p < 0.001) following transplantation. A significant improvement in performance was found in the BDNFtreated NSC group compared to the control group at 14, 21, and 28 (p < 0.05) days after transplantation. The cortex and hippocampus of the BDNF-treated NSC group had significantly more SC121 + NSCs (p = 0.0125, p = 0.0098), fewer FJC + neurons (p = 0.0370, p = 0.0285), and a higher percentage of NeuN + expression (p = 0.0354) in the cortex compared to the untreated NSC group. BDNF treatment of NSCs resulted in significantly greater migration to SDF-1, secretion of M-CSF, VEGF, and expression of CXCR4, VCAM-1, Thrombospondins 1 and 2, and BDNF. BDNF pretreatment of NSCs results in higher initial NSC engraftment and survival, increased neuroprotection, and greater functional recovery when compared to untreated NSCs.

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Section: Discussionmentioning

confidence: 99%

BDNF Pretreatment of Human Embryonic-Derived Neural Stem Cells Improves Cell Survival and Functional Recovery after Transplantation in Hypoxic–Ischemic Stroke

et al. 2015

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“…However, its ubiquitous expression in various cells suggests its diverse functions in different systems. NCAM was found to play a role in cell growth (Francavilla et al, 2009), tumor malignancy (Jensen and Berthold, 2007) and cell type segregation in pancreatic islets (Esni et al, 1999). The recent findings that adult stem cells and progenitor cells also express NCAM suggest its previously unknown function in stem cells (Evseenko et al, 2010;Kato et al, 2008;Wang et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Upon homophilic or heterophilic binding between cell and cell or cell and extracellular matrix, NCAM is able to activate a complex network of intracellular signaling cascades. It has been well documented that in neurite outgrowth, NCAM can activate fibroblast growth factor receptor (FGFR)-dependent or FGFR-independent signaling molecules, including Fyn, FAK, GAP-43, PLCg-PKC and PKA (Beggs et al, 1997;Francavilla et al, 2009;Kolkova et al, 2000). Therefore, NCAM is sometimes regarded as a functional receptor (such as a receptor for glial cell line-derived neurotrophic factor), rather than only a mechanical cell adhesion molecule (Jensen and Berthold, 2007;Paratcha et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

A novel role for neural cell adhesion molecule in modulating insulin signaling and adipocyte differentiation of mouse mesenchymal stem cells

Yang

Xia

Wang

et al. 2011

Journal of Cell Science

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SummaryNeural cell adhesion molecule (NCAM) has recently been found on adult stem cells, but its biological significance remains largely unknown. In this study, we used bone-marrow-derived mesenchymal stem cells (MSCs) from wild-type and NCAM knockout mice to investigate the role of NCAM in adipocyte differentiation. It was demonstrated that NCAM isoforms 180 and 140 but not NCAM-120 are expressed on almost all wild-type MSCs. Upon adipogenic induction, Ncam -/-MSCs exhibited a marked decrease in adipocyte differentiation compared with wild-type cells. The role of NCAM in adipocyte differentiation was also confirmed in NCAM-silenced preadipocyte 3T3-L1 cells, which also had a phenotype with reduced adipogenic potential. In addition, we found that Ncam -/-MSCs appeared to be insulin resistant, as shown by their impaired insulin signaling cascade, such as the activation of the insulin-IGF-1 receptor, PI3K-Akt and CREB pathways. The PI3K-Akt inhibitor, LY294002, completely blocked adipocyte differentiation of MSCs, unveiling that the reduced adipogenic potential of Ncam -/-MSCs is due to insulin resistance as a result of loss of NCAM function. Furthermore, insulin resistance of Ncam -/-MSCs was shown to be associated with induction of tumor necrosis factor  (TNF-), a key mediator of insulin resistance. Finally, we demonstrated that re-expression of NCAM-180, but not NCAM-140, inhibits induction of TNF- and thereby improves insulin resistance and adipogenic potential of Ncam -/-MSCs. Our results suggest a novel role of NCAM in promoting insulin signaling and adipocyte differentiation of adult stem cells. These findings raise the possibility of using NCAM intervention to improve insulin resistance.

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“…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). Two peptides derived from the NCAM FN1 and FN2 domains have been identified that can stimulate FGFR signaling and neurite outgrowth (52,54).…”

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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The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking

Abstract: Although FGF-2 causes the FGFR to be internalized and degraded, NCAM gets cells moving by stabilizing the receptor, promoting receptor recycling, and initiating a promigratory signaling cascade.

Cited by 113 publications

References 69 publications

BDNF Pretreatment of Human Embryonic-Derived Neural Stem Cells Improves Cell Survival and Functional Recovery after Transplantation in Hypoxic–Ischemic Stroke

BDNF Pretreatment of Human Embryonic-Derived Neural Stem Cells Improves Cell Survival and Functional Recovery after Transplantation in Hypoxic–Ischemic Stroke

A novel role for neural cell adhesion molecule in modulating insulin signaling and adipocyte differentiation of mouse mesenchymal stem cells

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

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