title: The conformational state of hERG1 channels determines integrin association, downstream signaling, and cancer progression.
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-go-go-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 β1integrin 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 β1integrin-hERG1 interaction. Although open hERG1 channels did not interact as strongly with β1integrins as did closed channels, current flow through hERG1 channels was necessary to activate the integrin-dependent phosphorylation of Tyr397in 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/β1integrin interaction was disrupted. We conclude that the interaction of β1integrins 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.
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.
authors.forename: Andrea
authors.identifier: http://orcid.org/0000-0002-9297-0527
authors.initials: A
authors.lastname: Becchetti
authors.affiliation: Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy.
authors.forename: Silvia
authors.identifier: http://orcid.org/0000-0002-1909-5957
authors.initials: S
authors.lastname: Crescioli
authors.affiliation: Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zanieri
authors.affiliation: Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Petroni
authors.affiliation: Consiglio Nazionale delle Ricerche-Istituto Nazionale di Ottica, Via N. Carrara 1, 50019 Sesto Fiorentino, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mercatelli
authors.affiliation: Physics of Life Processes, Huygens-Kamerlingh Onnes Laboratory, Leiden University, Niels Bohrweg 2, 2333 CA Leiden, Netherlands.
authors.forename: Stefano
authors.initials: S
authors.lastname: Coppola
authors.affiliation: Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy.
authors.forename: Luca
authors.identifier: http://orcid.org/0000-0002-6146-2124
authors.initials: L
authors.lastname: Gasparoli
authors.affiliation: Di.V.A.L. Toscana SRL, Via Madonna del Piano 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Amico
authors.affiliation: Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy.
authors.forename: Serena
authors.identifier: http://orcid.org/0000-0001-8861-8718
authors.initials: S
authors.lastname: Pillozzi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy.
authors.forename: Olivia
authors.initials: O
authors.lastname: Crociani
authors.affiliation: Di.V.A.L. Toscana SRL, Via Madonna del Piano 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Stefanini
authors.affiliation: Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Fiore
authors.affiliation: Di.V.A.L. Toscana SRL, Via Madonna del Piano 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Carraresi
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Morello
authors.affiliation: Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy.
authors.forename: Sagar
authors.initials: S
authors.lastname: Manoli
authors.affiliation: Department of Medical Sciences, University of Torino, Corso Dogliotti 14, 10126 Torino, Italy.
authors.forename: Maria Felice
authors.identifier: http://orcid.org/0000-0003-0944-6992
authors.initials: MF
authors.lastname: Brizzi
authors.affiliation: Department of Surgical Sciences, University of Torino, Corso Dogliotti 14, 10126 Torino, Italy.
authors.forename: Davide
authors.identifier: http://orcid.org/0000-0003-0015-6374
authors.initials: D
authors.lastname: Ricci
authors.affiliation: Department of Surgical Sciences, University of Torino, Corso Dogliotti 14, 10126 Torino, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Rinaldi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy.
authors.forename: Alessio
authors.identifier: http://orcid.org/0000-0002-0361-0950
authors.initials: A
authors.lastname: Masi
authors.affiliation: Physics of Life Processes, Huygens-Kamerlingh Onnes Laboratory, Leiden University, Niels Bohrweg 2, 2333 CA Leiden, Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Consiglio Nazionale delle Ricerche-Istituto Nazionale di Ottica, Via N. Carrara 1, 50019 Sesto Fiorentino, Italy.
authors.forename: Franco
authors.identifier: http://orcid.org/0000-0002-7844-4686
authors.initials: F
authors.lastname: Quercioli
authors.affiliation: Physics of Life Processes, Huygens-Kamerlingh Onnes Laboratory, Leiden University, Niels Bohrweg 2, 2333 CA Leiden, Netherlands.
authors.forename: Paola
authors.identifier: http://orcid.org/0000-0001-6427-4906
authors.initials: P
authors.lastname: Defilippi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy. annarosa.arcangeli@unifi.it.
authors.forename: Annarosa
authors.identifier: http://orcid.org/0000-0002-6317-9648
authors.initials: A
authors.lastname: Arcangeli
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D019012:Integrin beta1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008819:Mice, Nude; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D019012:Integrin beta1; C496884:KCNH1 protein, human