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: Univ Milano Bicocca, Dept Biotechnol & Biosci, Piazza Sci 2, I-20126 Milan, Italy; Univ Firenze, Dept Expt & Clin Med, Viale GB Morgagni 50, I-50134 Florence, Italy; Ist Nazl Ottica, CNR, Via N Carrara 1, I-50019 Sesto Fiorentino, Italy; Leiden Univ, Huygens Kamerlingh Onnes Lab, Phys Life Proc, Niels Bohrweg 2, NL-2333 CA Leiden, Netherlands; DiVAL Toscana SRL, Via Madonna Piano 6, I-50019 Sesto Fiorentino, Italy; Univ Torino, Dept Mol Biotechnol & Hlth Sci, Via Nizza 52, I-10126 Turin, Italy; Univ Torino, Dept Med Sci, Corso Dogliotti 14, I-10126 Turin, Italy; Univ Torino, Dept Surg Sci, Corso Dogliotti 14, I-10126 Turin, Italy; Inst Canc Res & Treatment, Str Prov 142, I-10060 Candiolo, Italy; Univ Firenze, Dept Neurosci Psychol Drug Res & Child Hlth, Sect Pharmacol & Toxicol, Viale Pieraccini 6, I-50134 Florence, 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: 53
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