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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HAVDI and INPISGQ sequences have been identified as functional binding motifs in extracellular domain 1 (ECD1) of N-cadherin. Cyclic peptides containing a tandem repeat of the individual motifs function as N-cadherin agonists and stimulate neurite outgrowth. We now show that the cyclic peptide N-Ac-CHAVDINGHAVDIC-NH2 (SW4) containing the HAVDI sequence in tandem is efficacious also in promoting the in vitro survival of several populations of central nervous system neurons in paradigms where fibroblast growth factor-2 (FGF-2) is active. SW4 supported the survival of rat postnatal cerebellar granule neurons plated in serum-free medium and limited the death of differentiated granule neurons induced to die by switch to low K+ medium. In addition, SW4 rescued embryonic hippocampal and cortical neurons from injury caused by glutamic acid excitotoxicity. The neuroprotective effects of SW4 displayed a concentration dependence similar to those inducing neuritogenesis, were inhibited by a monomeric version of the same motif and by a specific FGF receptor antagonist (PD173074), and were not mimicked by the linear peptide. Inhibitors of the phosphatidylinositol 3-kinase (PI 3-kinase), MAP kinase, and p38 kinase signalling pathways did not interfere with SW4 function. These data suggest that SW4 functions by binding to and clustering N-cadherin in neurons and thereby activating and N-cadherin/FGF receptor signalling cascade, and propose that such agonists may represent a starting point for the development of therapeutic agents promoting neuronal cell survival and regeneration.
Mol Cell Neurosci 2004 May
PMID:A dimeric version of the short N-cadherin binding motif HAVDI promotes neuronal cell survival by activating an N-cadherin/fibroblast growth factor receptor signalling cascade. 1512 Nov 75

We previously identified pituitary tumor-derived fibroblast growth factor receptor 4 (ptd-FGFR4), an alternatively transcribed N-terminally truncated cytoplasmic receptor isoform. Unlike wild-type FGFR4, ptd-FGFR4 facilitates cell transformation and results in pituitary tumor formation in transgenic mice. To investigate differences in the tumorigenic properties of FGFR4 and ptd-FGFR4, we examined their abilities to modulate cell adhesiveness. Introduction of ptd-FGFR4 into GH4 pituitary cells or NIH 3T3 fibroblasts resulted in significant reduction in cell adhesion to a collagen IV matrix compared with FGFR4- or empty vector-transfected cells. This adhesive difference was evident in the absence or presence of FGF stimulation. Furthermore, treatment with beta1-integrin neutralizing antibody markedly reduced adhesiveness in FGFR4-transfected cells but had little effect on the depressed adhesiveness of ptd-FGFR4-transfected cells. Unlike wild-type FGFR4, ptd-FGFR4 does not associate with neural cell-adhesion molecule (NCAM). Cells expressing FGFR4 demonstrate membranous N-cadherin with a noninvasive growth pattern identical to control GH4 cells when injected into immunodeficient mice. In contrast, ptd-FGFR4-expressing cells develop invasive tumors in vivo with marked loss of N-cadherin that localizes to the cytoplasm. Consistent with these changes, beta-catenin expression was diminished and its interaction with N-cadherin was disrupted in the presence of ptd-FGFR4, but both were intact in the presence of wild-type FGFR4. These data highlight the importance of membrane-anchored FGFR4 in assembling a multiprotein FGFR4 complex with NCAM and N-cadherin playing pivotal functions in maintaining normal cell adhesion. Disruption of distinct NCAM/N-cadherin proadhesive complexes by a tumor-derived FGFR4 isoform provides a novel mechanism beyond ligand independence that explains the pathobiology of proliferative and infiltrative but nonmetastatic neoplasms.
Mol Endocrinol 2004 Oct
PMID:Pituitary tumor-derived fibroblast growth factor receptor 4 isoform disrupts neural cell-adhesion molecule/N-cadherin signaling to diminish cell adhesiveness: a mechanism underlying pituitary neoplasia. 1523 74

Myofibroblasts of wound granulation tissue, in contrast to dermal fibroblasts, join stress fibers at sites of cadherin-type intercellular adherens junctions (AJs). However, the function of myofibroblast AJs, their molecular composition, and the mechanisms of their formation are largely unknown. We demonstrate that fibroblasts change cadherin expression from N-cadherin in early wounds to OB-cadherin in contractile wounds, populated with alpha-smooth muscle actin (alpha-SMA)-positive myofibroblasts. A similar shift occurs during myofibroblast differentiation in culture and seems to be responsible for the homotypic segregation of alpha-SMA-positive and -negative fibroblasts in suspension. AJs of plated myofibroblasts are reinforced by alpha-SMA-mediated contractile activity, resulting in high mechanical resistance as demonstrated by subjecting cell pairs to hydrodynamic forces in a flow chamber. A peptide that inhibits alpha-SMA-mediated contractile force causes the reorganization of large stripe-like AJs to belt-like contacts as shown for enhanced green fluorescent protein-alpha-catenin-transfected cells and is associated with a reduced mechanical resistance. Anti-OB-cadherin but not anti-N-cadherin peptides reduce the contraction of myofibroblast-populated collagen gels, suggesting that AJs are instrumental for myofibroblast contractile activity.
Mol Biol Cell 2004 Sep
PMID:Myofibroblast development is characterized by specific cell-cell adherens junctions. 1524 Aug 21

Under normal homeostasis, melanocyte growth and behaviour is tightly controlled by the surrounding keratinocytes. Keratinocytes regulate melanocyte behaviour through a complex system of paracrine growth factors and cell-cell adhesion molecules. Pathological changes, leading to development of malignant melanoma, upset this delicate homeostatic balance and can lead to altered expression of cell-cell adhesion and cell-cell communication molecules. In particular, there is a switch from the E-cadherin-mediated keratinocyte-melanocyte partnership to the N-cadherin-mediated melanoma-melanoma and melanoma-fibroblast interaction. Other changes include the alteration in the gap junctions formed between the melanocyte and keratinocyte. Changes in the connexin expression, in particular the loss of connexin 43, may result in a reduction or a loss of gap junctional activity, which is thought to contribute towards tumour progression. In the current review we describe the alterations in cell-cell adhesion and communication associated with melanoma development and progression, and discuss how a greater understanding of these processes may aid the future therapy of this disease.
J Mol Histol 2004 Mar
PMID:The role of altered cell-cell communication in melanoma progression. 1533 50

Skeletal muscle degeneration is a side effect of cholesterol-lowering hydroxymethylglutaryl coenzyme A reductase inhibitors. The expression of the cell-cell adhesion proteins, neural cell adhesion molecule and neural-cadherin was studied in a case of rhabdomyolysis induced by the hydroxymethylglutaryl coenzyme A reductase inhibitor cerivastatin. Neural cell adhesion molecule and N-cadherin participate in the interactions of muscle cells during skeletal myogenesis. In the adult muscle, neural cell adhesion molecule is restricted to neuromuscular sites but is re-expressed in denervated muscle and in rhabdomyolysis. Our results show expression of neural cell adhesion molecule in regenerative skeletal muscle fibers but not in degenerated or unaffected fibers in cerivastatin-induced rhabdomyolysis. In contrast, N-cadherin was not expressed. The presence of apoptotic cells was studied by a fluorescence-based Tdt-mediated dUTP nick-end labeling in the same sections. Apoptosis was detected in degenerative fibers and inflammatory cells but not in regenerative fibers. We hypothesize that the expression of neural cell adhesion molecule in regenerative fibers may have a protective role against apoptosis during rhabdomyolysis. Cerivastatin-induced rhabdomyolysis appears to have common features with rhabdomyolysis of other causes. The immunohistochemical study of neural cell adhesion molecule can serve as an additional tool in the evaluation of muscle regeneration in rhabdomyolysis.
Appl Immunohistochem Mol Morphol 2004 Sep
PMID:Overexpression of neural cell adhesion molecule in regenerative muscle fibers in 3-hydroxy-3-methylglutaryl coenzyme: A reductase inhibitor-induced rhabdomyolysis. 1555 37

It is widely acknowledged that cultured myoblasts can not differentiate at very low density. Here we analyzed the mechanism through which cell density influences myogenic differentiation in vitro. By comparing the behavior of C2C12 myoblasts at opposite cell densities, we found that, when cells are sparse, failure to undergo terminal differentiation is independent from cell cycle control and reflects the lack of p27Kip1 and MyoD in proliferating myoblasts. We show that inhibition of p27Kip1 expression impairs C2C12 cell differentiation at high density, while exogenous p27Kip1 allows low-density cultured C2C12 cells to enter the differentiative program by regulating MyoD levels in undifferentiated myoblasts. We also demonstrate that the early induction of p27Kip1 is a critical step of the N-cadherin-dependent signaling involved in myogenesis. Overall, our data support an active role of p27Kip1 in the decision of myoblasts to commit to terminal differentiation, distinct from the regulation of cell proliferation, and identify a pathway that, reasonably, operates in vivo during myogenesis and might be part of the phenomenon known as "community effect".
Mol Biol Cell 2005 Mar
PMID:p27Kip1 acts downstream of N-cadherin-mediated cell adhesion to promote myogenesis beyond cell cycle regulation. 1564 80

Olfactory ensheathing cells (OECs) and Schwann cells provide a cellular environment that promotes axonal outgrowth in several models of CNS injury. However, they exhibit different properties when in contact with astrocytes. Schwann cells, but not OECs, induce characteristics that typify hypertrophy in astrocytes and exhibit a poor capacity to migrate within astrocyte-rich areas, making them less favourable for transplant-mediated repair. N-cadherin has been implicated in the adhesion of Schwann cells to astrocytes. Despite indistinguishable expression of N-cadherin, Schwann cells adhered more strongly to an astrocyte monolayer and migrated more slowly on astrocytes when compared to OECs. We have examined the role of N-cadherin in mediating these cellular interactions using RNA interference and found differing effects. In Schwann cells, suppression of N-cadherin reduced heterotypic and homotypic adhesion and they gained adhesion properties more akin to OECs. In contrast, suppression of N-cadherin in OECs had no effect. These findings imply that N-cadherin is differentially regulated in OECs and Schwann cells.
Mol Cell Neurosci 2005 Feb
PMID:N-cadherin differentially determines Schwann cell and olfactory ensheathing cell adhesion and migration responses upon contact with astrocytes. 1569 7

Cadherins are homophilic cell-cell adhesion molecules implicated in cell growth, differentiation, and organization into tissues during embryonic development. They accumulate at cell-cell contact sites and act as adhesion-activated signaling receptors. Here, we show that the dynamic assembly of N-cadherin at cell-cell contacts involves lipid rafts. In C2C12 myoblasts, immunofluorescence and biochemical experiments demonstrate that N-cadherin present at cell-cell contacts is colocalized with lipid rafts. Disruption of lipid rafts leads to the inhibition of cell-cell adhesion and disorganization of N-cadherin-dependent cell-cell contacts without modifying the association of N-cadherin with catenins and its availability at the plasma membrane. Fluorescent recovery after photobleaching experiments demonstrate that at the dorsal plasma membrane, lipid rafts are not directly involved in the diffusional mobility of N-cadherin. In contrast, at cell-cell junctions N-cadherin association with lipid rafts allows its stabilization enabling the formation of a functional adhesive complex. We show that lipid rafts, as homophilic interaction and F-actin association, stabilize cadherin-dependent adhesive complexes. Homophilic interactions and F-actin association of N-cadherin are both required for its association to lipid rafts. We thus identify lipid rafts as new regulators of cadherin-mediated cell adhesion.
Mol Biol Cell 2005 May
PMID:N-cadherin association with lipid rafts regulates its dynamic assembly at cell-cell junctions in C2C12 myoblasts. 1571 54

We previously observed that cadherin-11, a type II cadherin, is expressed in growing motor and sensory axons in the mouse embryo. Here, we assessed its functional involvement in the regulation of axon elongation and fasciculation by evaluating the activity of a specific cadherin-11 homophilic ligand, cad11-Fc (cadherin-11 extracellular region fused to Fc fragment of IgG), on the length and organization of motor axons outgrowing from embryonic ventral spinal cord explants. Cad11-Fc substrate enhanced axon growth and prevented interactions occurring between growing axons, providing evidences for a role of cadherin-11 in the control of growth cone progression. Comparison of cadherin-11 with N-cadherin, a type I cadherin concomitantly expressed by motor axons, revealed similarities in their functional properties, including the ability to reorganize the actin cytoskeleton through interactions with catenins, but differences in their axon growth-promoting activity, arguing for subtle differences in their contributions to peripheral nerve elongation.
Mol Cell Neurosci 2005 Apr
PMID:A novel function for cadherin-11 in the regulation of motor axon elongation and fasciculation. 1579 18

Cell protrusions contribute to cell motility and migration by mediating the outward extension and initial adhesion of cell edges. In many cells, these extensions are supported by actin bundles assembled by the actin cross-linking protein, fascin. Multiple extracellular cues regulate fascin and here we focus on the mechanism by which the transmembrane proteoglycan, syndecan-1, specifically activates lamellipodial cell spreading and fascin-and-actin bundling when clustered either by thrombospondin-1, laminin, or antibody to the syndecan-1 extracellular domain. There is almost no knowledge of the signaling mechanisms of syndecan-1 cytoplasmic domain and we have tested the hypothesis that the unique V region of syndecan-1 cytoplasmic domain has a crucial role in these processes. By four criteria--the activities of N-cadherin/V region chimeras, syndecan-1 deletion mutants, or syndecan-1 point mutants, and specific inhibition by a membrane-permeable TAT-V peptide--we demonstrate that the V region is necessary and sufficient for these cell behaviors and map the molecular basis for its activity to multiple residues located across the V region. These activities correlate with a V-region-dependent incorporation of cell-surface syndecan-1 into a detergent-insoluble form. We also demonstrate functional roles of syndecan-1 V region in laminin-dependent C2C12 cell adhesion and three-dimensional cell migration. These data identify for the first time specific cell behaviors that depend on signaling through the V region of syndecan-1.
Mol Biol Cell 2005 Aug
PMID:Functional role of syndecan-1 cytoplasmic V region in lamellipodial spreading, actin bundling, and cell migration. 1593 Jan 35


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