Research ArticleCancer

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

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Sci. Signal.  04 Apr 2017:
Vol. 10, Issue 473, eaaf3236
DOI: 10.1126/scisignal.aaf3236

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Channeling proliferation or metastasis

The hERG1 potassium channel is best known for its role in repolarizing excitable cells such as cardiomyocytes, but the abundance of this cardiac channel is aberrantly high in cancer cells. Becchetti et al. investigated the interaction of hERG1 with the β1 integrin subunit, a member of a family of adhesion molecules. Forms of hERG1 with mutations that fixed the channel in the open conformation more weakly interacted with β1 integrin in cells and enhanced proliferation when expressed in breast cancer cells injected into mice. However, K+ flow through open hERG1 channels enhanced the activation of FAK downstream of β1 integrin and promoted metastasis in breast cancer cells injected into mice. Thus, whether hERG1 promotes proliferation or metastasis in cancer cells depends on the conformation of the channel and suggests that hERG1 inhibitors that are tailored to the channel conformation could be used to prevent different aspects of tumor 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 β1 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 β1 integrin–hERG1 interaction. Although open hERG1 channels did not interact as strongly with β1 integrins as did closed channels, current flow through hERG1 channels was necessary to activate the integrin-dependent phosphorylation of Tyr397 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/β1 integrin interaction was disrupted. We conclude that the interaction of β1 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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