Integrins regulate hERG1 dynamics by girdin-dependent Gαi3: signaling and modeling in cancer cells.
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| Abstract |
The hERG1 potassium channel is aberrantly over expressed in tumors and regulates the cancer cell response to integrin-dependent adhesion. We unravel a novel signaling pathway by which integrin engagement by the ECM protein fibronectin promotes hERG1 translocation to the plasma membrane and its association with β1 integrins, by activating girdin-dependent Gαi3 proteins and protein kinase B (Akt). By sequestering hERG1, β1 integrins make it avoid Rab5-mediated endocytosis, where unbound channels are degraded. The cycle of hERG1 expression determines the resting potential (Vrest) oscillations and drives the cortical f-actin dynamics and thus cell motility. To interpret the slow biphasic kinetics of hERG1/β1 integrin interplay, we developed a mathematical model based on a generic balanced inactivation-like module. Integrin-mediated cell adhesion triggers two contrary responses: a rapid stimulation of hERG1/β1 complex formation, followed by a slow inhibition which restores the initial condition. The protracted hERG1/β1 integrin cycle determines the slow time course and cyclic behavior of cell migration in cancer cells.
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| Authors | Claudia Duranti, Jessica Iorio, Giacomo Bagni, Ginevra Chioccioli Altadonna, Thibault Fillion, Matteo Lulli, Franco Nicolas D'Alessandro, Alberto Montalbano, Elena Lastraioli, Duccio Fanelli, Stefano Coppola, Thomas Schmidt, Francesco Piazza, Andrea Becchetti, Annarosa Arcangeli |
| Journal | Life science alliance (Life Sci Alliance) Vol. 7 Issue 1 (01 2024) ISSN: 2575-1077 [Electronic] United States |
| PMID | 37923359 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2023 Duranti et al. |
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