Identification of an N-cadherin Motif That Can Interact with the Fibroblast Growth Factor Receptor and Is Required for Axonal Growth

Williams, Emma-Jane; Williams, Gareth; Howell, Fiona V.; Skaper, Stephen D.; Walsh, Frank S.; Doherty, Patrick

doi:10.1074/jbc.m105876200

Cited by 134 publications

(133 citation statements)

References 43 publications

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“…Numerous studies have reported that cadherins interact with growth factor receptors, including VE-cadherin with vascular endothelial growth factor (VEGF) receptor, N-cadherin with FGF receptor, and E-cadherin with EGFR (Williams et al, 2001;Lampugnani et al, 2003;Qian et al, 2004). Cadherins have been found to influence growth factor receptor signaling, either activating (Pece and Gutkind, 2000) or inhibiting (Takahashi and Suzuki, 1996;Qian et al, 2004) signaling.…”

Section: Discussionmentioning

confidence: 99%

E-Cadherin Homophilic Ligation Inhibits Cell Growth and Epidermal Growth Factor Receptor Signaling Independently of Other Cell Interactions

Perrais

Chen

Pérez-Moreno

et al. 2007

MBoC

193

178

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E-cadherin function leads to the density-dependent contact inhibition of cell growth. Because cadherins control the overall state of cell contact, cytoskeletal organization, and the establishment of many other kinds of cell interactions, it remains unknown whether E-cadherin directly transduces growth inhibitory signals. To address this question, we have selectively formed E-cadherin homophilic bonds at the cell surface of isolated epithelial cells by using functionally active recombinant E-cadherin protein attached to microspheres. We find that E-cadherin ligation alone reduces the frequency of cells entering the S phase, demonstrating that E-cadherin ligation directly transduces growth inhibitory signals. E-cadherin binding to ␤-catenin is required for cell growth inhibition, but ␤-catenin/T-cell factor transcriptional activity is not involved in growth inhibition resulting from homophilic binding. Neither E-cadherin binding to p120-catenin nor ␤-catenin binding to ␣-catenin, and thereby the actin cytoskeleton, is required for growth inhibition. E-cadherin ligation also inhibits epidermal growth factor (EGF) receptor-mediated growth signaling by a ␤-catenin-dependent mechanism. It does not affect EGF receptor autophosphorylation or activation of ERK, but it inhibits transphosphorylation of Tyr845 and activation of signal transducers and activators of transcription 5. Thus, E-cadherin homophilic binding independent of other cell contacts directly transduces growth inhibition by a ␤-catenin-dependent mechanism that inhibits selective signaling functions of growth factor receptors. INTRODUCTIONCell-cell adhesion mediated by cadherins is fundamental for the differentiation and integrity of most adult tissues (Gumbiner, 1996(Gumbiner, , 2005. E-cadherin is a major constituent of polarized epithelial cell junctions, and it mediates cell adhesion through Ca 2ϩ -dependent homophilic interaction of its extracellular domain and interaction of its cytoplasmic domain with catenins. E-cadherin is also a tumor suppressor protein, because its loss of expression or function has been shown to be associated with tumorigenesis and tumor progression (Takeichi, 1993). Restoration of E-cadherin expression in cancer cells results in decreased invasiveness, growth suppression, and terminal differentiation (Behrens et al., 1989;Vleminckx et al., 1991;Perl et al., 1998;Gottardi et al., 2001;Wong and Gumbiner, 2003).Cadherins have also been postulated to be responsible for the phenomenon of contact inhibition of cell growth. Contact inhibition is a widely acknowledged property of cells in tissue , but the mechanisms that are responsible are not well understood. Although, there is evidence that cadherin expression can influence cell growth rates (Watabe et al., 1994;Caveda et al., 1996;St Croix et al., 1998;Mueller et al., 2000;Motti et al., 2005), their exact roles in contact inhibition are not well understood. A density-dependent inhibition of cell proliferation could result from many other factors that are indirectly influenced by the...

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Section: Discussionmentioning

confidence: 99%

E-Cadherin Homophilic Ligation Inhibits Cell Growth and Epidermal Growth Factor Receptor Signaling Independently of Other Cell Interactions

Perrais

Chen

Pérez-Moreno

et al. 2007

MBoC

193

178

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“…Moreover, myogenin expression required immobilized N-cadherin ligand, suggesting that the signaling activity of N-cadherin receptor is dependent on its adhesive engagement. Doherty and co-workers (47) reported that N-cadherin signaling associated to neurite outgrowth is triggered by soluble extracellular domain of N-cadherin involving fibroblast growth factor receptor clustering by direct binding of N-cadherin ectodomain. Although tyrosine kinase receptors (47,48) could be involved in the present response to N-cadherin activation, we favor a signaling pathway through the cadherin-associated catenins in the myogenic context.…”

Section: Discussionmentioning

confidence: 99%

N-cadherin Activation Substitutes for the Cell Contact Control in Cell Cycle Arrest and Myogenic Differentiation

Gavard

Marthiens

Monnet

et al. 2004

Journal of Biological Chemistry

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N-cadherin is expressed throughout skeletal myogenesis and has been proposed to be involved in the differentiation program of myogenic precursors. Here, we further characterize the N-cadherin involvement and its mechanism of action at the onset of differentiation, through controlled N-cadherin activation by plating isolated C2 myoblasts on surfaces coated with a chimeric Ncad-Fc homophilic ligand (N-cadherin ectodomain fused to the immunoglobulin G Fc fragment). We show that N-cadherin activation substitutes for the cell density in myogenic differentiation by promoting myogenin and troponin T expression. In addition, N-cadherin adhesion participates to the associated cell cycle arrest through the nuclear accumulation of cyclin-dependent kinase inhibitors p21 and p27. Mouse primary myoblast cultures exhibited similar responses to N-cadherin as C2 cells. RNA interference knockdowns of the N-cadherinassociated cytoplasmic proteins p120 and ␤-catenin produced opposite effects on the differentiation pathway. p120 silencing resulted in a decreased myogenic differentiation, associated with a reduction in cadherin-catenin content, which may explain its action on myogenic differentiation. ␤-Catenin silencing led to a stimulatory effect on myogenin expression, without any effect on cell cycle. Our results demonstrate that N-cadherin adhesion may account for cell-cell contact-dependent cell cycle arrest and differentiation of myogenic cells, involving regulation through p120 and ␤-catenins.

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“…The interaction between N-cadherin and FGFR leads to stabilization of FGFR at the membrane surface by preventing its internalization upon ligand binding. As a result, sustained MAPK pathway activation and increased cell motility and MMP secretion promote invasiveness of N-cadherin-expressing cells [96][97][98]. NCAM accomplishes a similar induction of cell migration and invasion by directly binding and stimulating FGFR via its fibronectin type III domains [95].…”

Section: The Cadherin Switch and Its Consequencesmentioning

confidence: 99%

EMT, the cytoskeleton, and cancer cell invasion

Yilmaz

Christofori

2009

Cancer Metastasis Rev

1,534

1,314

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The metastatic process, i.e. the dissemination of cancer cells throughout the body to seed secondary tumors at distant sites, requires cancer cells to leave the primary tumor and to acquire migratory and invasive capabilities. In a process of epithelial-mesenchymal transition (EMT), besides changing their adhesive repertoire, cancer cells employ developmental processes to gain migratory and invasive properties that involve a dramatic reorganization of the actin cytoskeleton and the concomitant formation of membrane protrusions required for invasive growth. The molecular processes underlying such cellular changes are still only poorly understood, and the various migratory organelles, including lamellipodia, filopodia, invadopodia and podosomes, still require a better functional and molecular characterization. Notably, direct experimental evidence linking the formation of migratory membrane protrusions and the process of EMT and tumor metastasis is still lacking. In this review, we have summarized recent novel insights into the molecular processes and players underlying EMT on one side and the formation of invasive membrane protrusions on the other side.

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Identification of an N-cadherin Motif That Can Interact with the Fibroblast Growth Factor Receptor and Is Required for Axonal Growth

Cited by 134 publications

References 43 publications

E-Cadherin Homophilic Ligation Inhibits Cell Growth and Epidermal Growth Factor Receptor Signaling Independently of Other Cell Interactions

E-Cadherin Homophilic Ligation Inhibits Cell Growth and Epidermal Growth Factor Receptor Signaling Independently of Other Cell Interactions

N-cadherin Activation Substitutes for the Cell Contact Control in Cell Cycle Arrest and Myogenic Differentiation

EMT, the cytoskeleton, and cancer cell invasion

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