HERG1 Channels In Cancer Cells: Physical and Functional Interaction With Integrin Receptors

Abstract

The expression and activity of different channel types mark and regulate specific stages of cancer progression, from cell proliferation and apoptosis, to invasiveness, angiogenesis and metastatic spread. As is being increasingly recognized, some of these roles can be attributed to signaling mechanisms independent of ion flow. Evidence is particularly extensive for K+ channels. For example, intracellular signaling cascades can be triggered when ion channels form protein complexes with other membrane proteins such as integrins or growth factor receptors.Work in our lab has established that hERG1 K+ channels are often aberrantly expressed in primary human cancers and exert pleiotropic effects in cancer cells, in turn regulating cell proliferation, cell motility and invasiveness or stimulating the process of neo-angiogenesis. hERG1 can induce such diverse effects since it triggers and modulates intracellular signaling cascades. This role depends on the formation, on the plasma membrane of tumor cells, of macromolecular complexes with integrin receptors, in particular with the β1 subunit. Recent FRET experiments have clearly shown that hERG1 and β1 directly interact, the intermolecular distance between the two proteins being around 4 nm. Moreover, the hERG1 protein inside the complex could function differently from its classical role in excitable cells, i.e. independently of ion flux, but through a conformational coupling with the partner protein(s). On the whole, data gathered so far allow us to propose a novel antineoplastic therapeutical approach, based on the targeting and unlocking of the β1 /hERG1 complex, in order to impair the hERG1-mediated signaling in cancer cells.