Human ether-a-go-go-related gene 1 channels are physically linked to β 1 integrins and modulate adhesion-dependent signaling

Alessia Cherubini, Giovanna Hofmann, Serena Pillozzi, Leonardo Guasti, Olivia Crociani, Emanuele Cilia, Paola Di Stefano, Simona Degani, Manuela Balzi, Massimo Olivotto, Enzo Wanke, Andrea Becchetti, Paola Defilippi, Randy Wymore, Annarosa Arcangeli

Research output: Contribution to journalArticle

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Abstract

Adhesive receptors of the integrin family are primarily involved in cell-extracellular matrix adhesion. Additionally, integrins trigger multiple signaling pathways that are involved in cell migration, proliferation, survival, and differentiation. We previously demonstrated that the activation of integrins containing the β 1, subunit leads to a selective increase in potassium currents carried by the human ether-a-go-go-related gene (hERG) channels in neuroblastoma and leukemia cells; this current activation modulates adhesion-dependent differentiation in these cells. We hypothesized that the cross-talk between integrins and hERG channels could be traced back to the assembly of a macromolecular signaling complex comprising the two proteins. We tested this hypothesis in both SH-SY5Y neuroblastoma cells and in human embryonic kidney 293 cells stably transfected with hERG1 and, therefore, expressing only the full-length hERG1 protein on the plasma membrane. The β 1 integrin and hERG1 coprecipitate in these cells and colocalize in both intracellular and surface membrane compartments. The two proteins also coprecipitate with caveolin-1, suggesting the localization of the complex in lipid rafts/caveolae. hERG1-transfected cells undergo an activation of hERG currents after β 1 integrin-mediated adhesion to fibronectin; concomitant with this activation, the focal adhesion kinase associates with the hERG1 protein and becomes tyrosine phosphorylated. Using hERG1-specific inhibitors, we show that the tyrosine phosphorylation of focal adhesion kinase is strictly dependent on hERG channel activity. Similarly, the activity of the small GTPase Rac1 turned out to be dependent on hERG currents. On the whole, these data indicate that the hERG1 protein associates with β 1 integrins and modulates adhesion receptor signaling.

Original languageEnglish
Pages (from-to)2972-2983
Number of pages12
JournalMolecular Biology of the Cell
Volume16
Issue number6
DOIs
StatePublished - 9 Jun 2005

Fingerprint

Integrins
Ether
Genes
Focal Adhesion Protein-Tyrosine Kinases
Proteins
Neuroblastoma
Tyrosine
Cell-Matrix Junctions
Macromolecular Substances
Caveolin 1
Caveolae
Intracellular Membranes
Monomeric GTP-Binding Proteins
Fibronectins
Adhesives
Cell Movement
Extracellular Matrix
Cell Differentiation
Potassium
Leukemia

Cite this

Cherubini, Alessia ; Hofmann, Giovanna ; Pillozzi, Serena ; Guasti, Leonardo ; Crociani, Olivia ; Cilia, Emanuele ; Di Stefano, Paola ; Degani, Simona ; Balzi, Manuela ; Olivotto, Massimo ; Wanke, Enzo ; Becchetti, Andrea ; Defilippi, Paola ; Wymore, Randy ; Arcangeli, Annarosa. / Human ether-a-go-go-related gene 1 channels are physically linked to β 1 integrins and modulate adhesion-dependent signaling. In: Molecular Biology of the Cell. 2005 ; Vol. 16, No. 6. pp. 2972-2983.
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abstract = "Adhesive receptors of the integrin family are primarily involved in cell-extracellular matrix adhesion. Additionally, integrins trigger multiple signaling pathways that are involved in cell migration, proliferation, survival, and differentiation. We previously demonstrated that the activation of integrins containing the β 1, subunit leads to a selective increase in potassium currents carried by the human ether-a-go-go-related gene (hERG) channels in neuroblastoma and leukemia cells; this current activation modulates adhesion-dependent differentiation in these cells. We hypothesized that the cross-talk between integrins and hERG channels could be traced back to the assembly of a macromolecular signaling complex comprising the two proteins. We tested this hypothesis in both SH-SY5Y neuroblastoma cells and in human embryonic kidney 293 cells stably transfected with hERG1 and, therefore, expressing only the full-length hERG1 protein on the plasma membrane. The β 1 integrin and hERG1 coprecipitate in these cells and colocalize in both intracellular and surface membrane compartments. The two proteins also coprecipitate with caveolin-1, suggesting the localization of the complex in lipid rafts/caveolae. hERG1-transfected cells undergo an activation of hERG currents after β 1 integrin-mediated adhesion to fibronectin; concomitant with this activation, the focal adhesion kinase associates with the hERG1 protein and becomes tyrosine phosphorylated. Using hERG1-specific inhibitors, we show that the tyrosine phosphorylation of focal adhesion kinase is strictly dependent on hERG channel activity. Similarly, the activity of the small GTPase Rac1 turned out to be dependent on hERG currents. On the whole, these data indicate that the hERG1 protein associates with β 1 integrins and modulates adhesion receptor signaling.",
author = "Alessia Cherubini and Giovanna Hofmann and Serena Pillozzi and Leonardo Guasti and Olivia Crociani and Emanuele Cilia and {Di Stefano}, Paola and Simona Degani and Manuela Balzi and Massimo Olivotto and Enzo Wanke and Andrea Becchetti and Paola Defilippi and Randy Wymore and Annarosa Arcangeli",
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Cherubini, A, Hofmann, G, Pillozzi, S, Guasti, L, Crociani, O, Cilia, E, Di Stefano, P, Degani, S, Balzi, M, Olivotto, M, Wanke, E, Becchetti, A, Defilippi, P, Wymore, R & Arcangeli, A 2005, 'Human ether-a-go-go-related gene 1 channels are physically linked to β 1 integrins and modulate adhesion-dependent signaling', Molecular Biology of the Cell, vol. 16, no. 6, pp. 2972-2983. https://doi.org/10.1091/mbc.E04-10-0940

Human ether-a-go-go-related gene 1 channels are physically linked to β 1 integrins and modulate adhesion-dependent signaling. / Cherubini, Alessia; Hofmann, Giovanna; Pillozzi, Serena; Guasti, Leonardo; Crociani, Olivia; Cilia, Emanuele; Di Stefano, Paola; Degani, Simona; Balzi, Manuela; Olivotto, Massimo; Wanke, Enzo; Becchetti, Andrea; Defilippi, Paola; Wymore, Randy; Arcangeli, Annarosa.

In: Molecular Biology of the Cell, Vol. 16, No. 6, 09.06.2005, p. 2972-2983.

Research output: Contribution to journalArticle

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T1 - Human ether-a-go-go-related gene 1 channels are physically linked to β 1 integrins and modulate adhesion-dependent signaling

AU - Cherubini, Alessia

AU - Hofmann, Giovanna

AU - Pillozzi, Serena

AU - Guasti, Leonardo

AU - Crociani, Olivia

AU - Cilia, Emanuele

AU - Di Stefano, Paola

AU - Degani, Simona

AU - Balzi, Manuela

AU - Olivotto, Massimo

AU - Wanke, Enzo

AU - Becchetti, Andrea

AU - Defilippi, Paola

AU - Wymore, Randy

AU - Arcangeli, Annarosa

PY - 2005/6/9

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N2 - Adhesive receptors of the integrin family are primarily involved in cell-extracellular matrix adhesion. Additionally, integrins trigger multiple signaling pathways that are involved in cell migration, proliferation, survival, and differentiation. We previously demonstrated that the activation of integrins containing the β 1, subunit leads to a selective increase in potassium currents carried by the human ether-a-go-go-related gene (hERG) channels in neuroblastoma and leukemia cells; this current activation modulates adhesion-dependent differentiation in these cells. We hypothesized that the cross-talk between integrins and hERG channels could be traced back to the assembly of a macromolecular signaling complex comprising the two proteins. We tested this hypothesis in both SH-SY5Y neuroblastoma cells and in human embryonic kidney 293 cells stably transfected with hERG1 and, therefore, expressing only the full-length hERG1 protein on the plasma membrane. The β 1 integrin and hERG1 coprecipitate in these cells and colocalize in both intracellular and surface membrane compartments. The two proteins also coprecipitate with caveolin-1, suggesting the localization of the complex in lipid rafts/caveolae. hERG1-transfected cells undergo an activation of hERG currents after β 1 integrin-mediated adhesion to fibronectin; concomitant with this activation, the focal adhesion kinase associates with the hERG1 protein and becomes tyrosine phosphorylated. Using hERG1-specific inhibitors, we show that the tyrosine phosphorylation of focal adhesion kinase is strictly dependent on hERG channel activity. Similarly, the activity of the small GTPase Rac1 turned out to be dependent on hERG currents. On the whole, these data indicate that the hERG1 protein associates with β 1 integrins and modulates adhesion receptor signaling.

AB - Adhesive receptors of the integrin family are primarily involved in cell-extracellular matrix adhesion. Additionally, integrins trigger multiple signaling pathways that are involved in cell migration, proliferation, survival, and differentiation. We previously demonstrated that the activation of integrins containing the β 1, subunit leads to a selective increase in potassium currents carried by the human ether-a-go-go-related gene (hERG) channels in neuroblastoma and leukemia cells; this current activation modulates adhesion-dependent differentiation in these cells. We hypothesized that the cross-talk between integrins and hERG channels could be traced back to the assembly of a macromolecular signaling complex comprising the two proteins. We tested this hypothesis in both SH-SY5Y neuroblastoma cells and in human embryonic kidney 293 cells stably transfected with hERG1 and, therefore, expressing only the full-length hERG1 protein on the plasma membrane. The β 1 integrin and hERG1 coprecipitate in these cells and colocalize in both intracellular and surface membrane compartments. The two proteins also coprecipitate with caveolin-1, suggesting the localization of the complex in lipid rafts/caveolae. hERG1-transfected cells undergo an activation of hERG currents after β 1 integrin-mediated adhesion to fibronectin; concomitant with this activation, the focal adhesion kinase associates with the hERG1 protein and becomes tyrosine phosphorylated. Using hERG1-specific inhibitors, we show that the tyrosine phosphorylation of focal adhesion kinase is strictly dependent on hERG channel activity. Similarly, the activity of the small GTPase Rac1 turned out to be dependent on hERG currents. On the whole, these data indicate that the hERG1 protein associates with β 1 integrins and modulates adhesion receptor signaling.

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