Non-canonical Activation of RSK1 Induces EphA2-Mediated Cell Migration under Cellular Stress Conditions

p90 ribosomal S6 kinase 1 (RSK1) regulates various cellular events involved in cell growth and migration. We previously demonstrated that RSK1 catalyzes Ephrin Receptor A2 (EphA2) phosphorylation at Ser-897 to promote Cancer cell migration, and that this pathway is regulated independently by extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2). Although the activation mechanism of RSK1 via ERK has been extensively examined, the mechanism for MK2 remains unclear. In the present study, we showed that MK2-mediated phosphorylation at Ser-380 in the linker region, a key mechanism of RSK1 activation, was dependent on the basal phosphorylation of Ser-221 in the N-terminal kinase domain. This basal phosphorylation was catalyzed by 3-phosphoinositide-dependent kinase 1 (PDK1) and was independent of ERK-catalyzed Ser-380 phosphorylation. The PDK1-MK2-RSK1-EphA2 axis promoted glioblastoma cell migration induced by temozolomide, a chemotherapeutic agent. Collectively, these results reveal a novel activation mechanism of RSK1 in Cancer malignancy.