Cadherin-Cadherin Engagement Promotes Cell Survival via Rac1/Cdc42 and Signal Transducer and Activator of Transcription-3

Arulanandam, Rozanne; Vultur, Adina; Cao, Jun; Carefoot, Esther; Elliott, Bruce E.; Truesdell, Peter; Larue, Lionel; Feracci, Hélène; Raptis, Leda

doi:10.1158/1541-7786.mcr-08-0469

Cited by 48 publications

(76 citation statements)

References 50 publications

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“…In epithelial cells, cell survival is regulated by a signaling cascade involving Par6 and GSK-3b (43), both of which are known to function in conjunction with Cdc42 to regulate cell polarity (17,44). Cdc42 was also found to be required for cell survival induced by Ecadherin homophilic interactions via activation of Stat3 (45). As LCs are dispersed throughout the epidermis in a distinct pattern maintained by E-cadherin-mediated adhesion to neighboring keratinocytes (46,47), it is plausible that this interaction plays a role in their survival in the steady state.…”

Section: Discussionmentioning

confidence: 99%

Rho-Family GTPase Cdc42 Controls Migration of Langerhans Cells In Vivo

Luckashenak

Wähe

Breit

et al. 2013

The Journal of Immunology

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Epidermal Langerhans cells (LCs) of the skin represent the prototype migratory dendritic cell (DC) subtype. In the skin, they take up Ag, migrate to the draining lymph nodes, and contribute to Ag transport and immunity. Different depletion models for LCs have revealed contrasting roles and contributions of this cell type. To target the migratory properties of DCs, we generated mice lacking the Rho-family GTPase Cdc42 specifically in DCs. In these animals, the initial seeding of the epidermis with LCs is functional, resulting in slightly reduced Langerhans cell numbers. However, Cdc42-deficient LCs fail to leave the skin in steady state as well as upon stimulation, as they do not enter the skin-draining afferent lymph vessels. Similarly, also other Cdc42-deficient migratory DC subsets fail to home properly to the corresponding draining lymph nodes. We used this novel mouse model, in which LCs are locked out, to demonstrate that these cells contribute substantially to priming of Ag-specific CD4 and CD8 T cell responses upon epicutaneous immunization, but could not detect a role in the induction of contact hypersensitivity to various doses of hapten.

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Section: Discussionmentioning

confidence: 99%

Rho-Family GTPase Cdc42 Controls Migration of Langerhans Cells In Vivo

Luckashenak

Wähe

Breit

et al. 2013

The Journal of Immunology

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“…This provides further evidence that E-cadherin is crucial for transduction of the Lif signal by stabilizing the LifrGp130 co-receptor complex. Interestingly, in mammary epithelial cells, E-cadherin-mediated cell adhesion was shown to promote Stat3 phosphorylation (Arulanandam et al, 2009). However, when these authors competitively disrupted the cell-cell contacts with the help of a recombinant E-cadherin fragment that included the two distal extracellular domains of E-cadherin, pStat3 levels decreased.…”

Section: Thus Ctnnb1mentioning

confidence: 99%

E-cadherin is required for the proper activation of the Lifr/Gp130 signaling pathway in mouse embryonic stem cells

et al. 2013

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SUMMARYThe leukemia inhibitory factor (Lif) signaling pathway is a crucial determinant for mouse embryonic stem (mES) cell self-renewal and pluripotency. One of the hallmarks of mES cells, their compact growth morphology, results from tight cell adhesion mediated through E-cadherin, β-catenin (Ctnnb1) and α-catenin with the actin cytoskeleton. β-catenin is also involved in canonical Wnt signaling, which has also been suggested to control mES cell stemness. Here, we analyze Ctnnb1 −/− mES cells in which cell adhesion is preserved by anEα mES cells), and show that mimicking only the adhesive function of β-catenin is necessary and sufficient to maintain the mES cell state, making β-catenin/Wnt signaling obsolete in this process. Furthermore, we propose a role for E-cadherin in promoting the Lif signaling cascade, showing an association of E-cadherin with the Lifr-Gp130 receptor complex, which is most likely facilitated by the extracellular domain of E-cadherin. Without Eα, and thus without maintained cell adhesion, Ctnnb1 −/− mES cells downregulate components of the Lif signaling pathway, such as Lifr, Gp130 and activated Stat3, as well as pluripotency-associated markers. From these observations, we hypothesize that the changes in gene expression accompanying the loss of pluripotency are a direct consequence of dysfunctional cell adhesion. Supporting this view, we find that the requirement for intact adhesion can be circumvented by the forced expression of constitutively active Stat3. In summary, we put forward a model in which mES cells can be propagated in culture in the absence of Ctnnb1, as long as E-cadherin-mediated cell adhesion is preserved.

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“…For instance cadherin engagement has been shown to promote tumor cell survival via activation of Rho-family GTPases that furthermore transduce the signal to transcription factors, such as the signal transducer and activator of transcription-3 (39). Signal transducer and activator of transcription-3 activity is routinely observed in cancers by promoting cell proliferation and preventing apoptosis (40).…”

Section: Figmentioning

confidence: 99%

Cadherin Engagement Protects Human β-Cells from Apoptosis

et al. 2011

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The aim of this study was to assess the expression of different types of cadherins in human islets and their role in human β-cell apoptosis. Expression of E-, N-, and P-cadherins was studied by immunofluorescence on pancreas sections and islet cells, and by Western blotting on protein extracts of isolated islets and islet cells. The effects of specific cadherins on cell adhesion and apoptosis were studied using chimeric proteins containing functional E-, N-, or P-cadherin ectodomains fused to Fc fragment of Ig (E-cad/Fc, N-cad/Fc, and P-cad/Fc) and immobilized on glass substrate. β-Cells were identified by immunofluorescence for insulin and apoptotic cells by terminal deoxynucleotide transferase-mediated 2'-deoxyuridine, 5'-triphosphate nick-end labeling. By immunofluorescence, we showed that E- and N-, and not P-, cadherins were expressed at the surface of islet cells. By triple staining, we showed that E-cadherin was expressed at similar extent in β- and α-cells, whereas N-cadherin was preferentially expressed in β-cells. These results were confirmed by Western blot analysis using protein extracts from fluorescence-activated cell sorting-sorted β- and non-β-cells. Adhesion tests showed that the affinity of islet cells for E-cad/Fc and N-cad/Fc and not for P-cad/Fc was increased compared with control. By terminal deoxynucleotide transferase-mediated 2'-deoxyuridine, 5'-triphosphate nick-end labeling, we showed that the percentage of apoptotic cells was lower in aggregated β-cells compared with single β-cells and that attachment to E-cad/Fc and N-cad/Fc and not to P-cad/Fc decreased apoptosis of single β-cells compared with control. Our results show that at least E- and N-cadherins are expressed at the surface of human β-cells and that these adhesion molecules are involved in the maintenance of β-cell viability.

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Cadherin-Cadherin Engagement Promotes Cell Survival via Rac1/Cdc42 and Signal Transducer and Activator of Transcription-3

Cited by 48 publications

References 50 publications

Rho-Family GTPase Cdc42 Controls Migration of Langerhans Cells In Vivo

Rho-Family GTPase Cdc42 Controls Migration of Langerhans Cells In Vivo

E-cadherin is required for the proper activation of the Lifr/Gp130 signaling pathway in mouse embryonic stem cells

Cadherin Engagement Protects Human β-Cells from Apoptosis

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