期刊
SCIENCE SIGNALING
卷 10, 期 473, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aaf3236
关键词
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资金
- Associazione Italiana per la Ricerca sul Cancro [10275, 15627]
- Association for International Cancer Research [06-0491]
- IonTraC Grant FP7-People-ITN [289648]
- Associazione Genitori Noi per Voi
- FRRB-Nanofarmaci
- University of Milano-Bicocca
- University of Firenze
- Italian Foundation for Cancer Research Fellowship [16334]
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-a-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 beta(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 beta(1) integrin-hERG1 interaction. Although open hERG1 channels did not interact as strongly with beta(1) integrins as did closed channels, current flow through hERG1 channels was 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/beta(1) integrin interaction was disrupted. We conclude that the interaction of beta(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.
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