Scientific Results

The conformational state of hERG1 channels determines integrin association, downstream signaling, and cancer progression

Year: 2017

Authors: Becchetti A., Crescioli S., Zanieri F., Petroni G., Mercatelli R., Coppola S., Gasparoli L., D\’Amico M., Pillozzi S., Crociani O., Stefanini M., Fiore A., Carraresi L., Morello V., Manoli S., Brizzi M.F., Ricci D., Rinaldi M., Masi A., Schmidt T., Quercioli F., Defilippi P., Arcangeli A.

Autors Affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, I-Milano, 20126, Italy; Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, Firenze, 50134, Italy; Consiglio Nazionale Delle Ricerche-Istituto Nazionale DiOttica, Via N. Carrara 1, Sesto Fiorentino, 50019, Italy; Physics of Life Processes, Huygens-Kamerlingh Onnes Laboratory, Leiden University, Niels Bohrweg 2, Leiden, 2333 CA, Netherlands; Di.V.A.L. Toscana SRL, Via Madonna del Piano 6, Sesto Fiorentino, 50019, Italy; Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, Torino, 10126, Italy; Department of Medical Sciences, University of Torino, Corso Dogliotti 14, Torino, 10126, Italy; Department of Surgical Sciences, University of Torino, Corso Dogliotti 14, Torino, 10126, Italy; Institute for Cancer Research and Treatment, Strada Provinciale 142, Candiolo, 10060, Italy; Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Firenze, Viale Pieraccini 6, Firenze, 50134, Italy

Abstract: Ion channels regulate cell proliferation, differentiation, and migration in normal and neoplastic cells through cell-cell and cell-extracellular matrix (ECM) transmembrane receptors called integrins. K + flux through the human ether-à-gogo- related gene 1 (hERG1) channel shapes action potential firing in excitable cells such as cardiomyocytes. Its abundance is often aberrantly high in tumors, where it modulates integrin-mediated signaling. We found that hERG1 interacted with the ß 1 integrin subunit at the plasma membrane of human cancer cells. This interaction was not detected in cardiomyocytes because of the presence of the hERG1 auxiliary subunit KCNE1 (potassium voltage-gated channel subfamily E regulatory subunit 1), which blocked the ß 1 integrin-hERG1 interaction. Although open hERG1 channels did not interact as strongly with ß 1 integrins as did closed channels, current flow through hERG1 channelswas necessary to activate the integrin-dependent phosphorylation of Tyr 397 in focal adhesion kinase (FAK) in both normal and cancer cells. In immunodeficient mice, proliferation was inhibited in breast cancer cells expressing forms of hERG1 with impaired K + flow, whereas metastasis of breast cancer cells was reduced when the hERG1/ß 1 integrin interaction was disrupted. We conclude that the interaction of ß 1 integrins with hERG1 channels in cancer cells stimulated distinct signaling pathways that depended on the conformational state of hERG1 and affected different aspects of tumor progression.

Journal/Review: SCIENCE SIGNALING

Volume: 10 (473)      Pages from: eaaf3236-1  to: eaaf3236-13

More Information: This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (#10275 and #15627 to A.A.), the Association for International Cancer Research (#06-0491 to A.A.), IonTraC Grant FP7-People-2011-ITN (#289648 to A.A. and fellowship to S.M.), Associazione Genitori Noi per Voi (to A.A.), FRRB-Nanofarmaci and the University of Milano-Bicocca (to A.B.), the University of Firenze (to A.A.), and the Italian Foundation for Cancer Research Fellowship (#16334 to S.C.).
KeyWords: Animals; Cell Line, Tumor; Disease progression; Ether-A-Go-Go Potassium Channels; Fluorescence Resonance Energy Transfer; HCT116 Cells; HEK293 Cells; Humans; Immunoblotting; Integrin beta1; Mice, Nude; Mice, SCID; Microscopy, Confocal; Neoplasms; Protein Binding; Protein Conformation; Signal transduction; Transplantation, heterologous
DOI: 10.1126/scisignal.aaf3236

Citations: 17
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