Rôle de la GTPase ARF6 dans la prolifération cellulaire
Although it is vital in normal physiological conditions, cell proliferation, when poorly controlled, could contribute to the pathogenesis and progression of serious diseases such as atherosclerosis and cancer. In this study, we demonstrate that the GTPase ARF6, classically known for its role in endocytosis, plasma membrane-endosomal trafficking and actin remodeling, controls cell proliferation at two different levels of the cell cycle, G1 phase and mitosis. First, in a cardiovascular context, we show that ARF6 controls AngII-induced ROS production by positively regulating Rac1 activation and NOX1 expression. ROS act as mediators to promote the transactivation of EGFR and the activation of the three MAP Kinases ERK1/2, p38MAPK and JNK1/2 inducing the expression of genes required for G1/S transition and proliferation. Second, we show that ARF6 plays an important role in the last phase of the cell cycle, mitosis. Indeed, ARF6 is required for the stability of microtubules (K-fibres) and the proper positioning of chromosomes at the metaphase plate allowing SAC satisfaction, triggering of cyclin B ubiquitination, its degradation and chromosomal segregation (anaphase). Finally, by studying the mTOR pathway in ARF6 depleted cells, we characterized a new regulation of this pathway during mitosis. We demonstrate that the kinases p85S6K1 and S6K2 are activated in a CDK1-dependent manner to phosphorylate the ribosomal protein S6 during mitosis.
ARF6 ROS Microtubules MTOR CDK1 Proliferation Mitosis Metaphase Kinetochores