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.
Integrins regulate hERG1 dynamics by girdin-dependent Gαi3: signaling and modeling in cancer cells / Duranti, Claudia; Iorio, Jessica; Bagni, Giacomo; Chioccioli Altadonna, Ginevra; Fillion, Thibault; Lulli, Matteo; D'Alessandro, Franco Nicolas; Montalbano, Alberto; Lastraioli, Elena; Fanelli, Duccio; Coppola, Stefano; Schmidt, Thomas; Piazza, Francesco; Becchetti, Andrea; Arcangeli, Annarosa. - In: LIFE SCIENCE ALLIANCE. - ISSN 2575-1077. - ELETTRONICO. - 7:(2023), pp. e202302135.1-e202302135.26. [10.26508/lsa.202302135]
Integrins regulate hERG1 dynamics by girdin-dependent Gαi3: signaling and modeling in cancer cells
Duranti, Claudia;Iorio, Jessica;Bagni, Giacomo;Chioccioli Altadonna, Ginevra;Lulli, Matteo;D'Alessandro, Franco Nicolas;Montalbano, Alberto;Lastraioli, Elena;Fanelli, Duccio;Piazza, Francesco;Arcangeli, Annarosa
2023
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.File | Dimensione | Formato | |
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