The Regulation of Integrin Activation and Recycling by RSK2 Promotes Cancer Migration and Invasion

Abstract

Integrins are cell-surface receptors that mediate cellular processes that occur during development and in the progression of disease such as cancer. Integrins signal bidirectionally across the plasma membrane. Outside-in signaling is activated upon ligation of integrins to ECM molecules and elicits intracellular responses to environmental cues. Inside-out signaling cascades, such as the RAS MAPK pathway, modulate the affinity of integrins for their ligands and therefore, regulate integrin activation. RSK2 functions downstream of the RAS and mediates several biological functions of the RAS MAPK pathway, such as the cell cycle, proliferation, and survival. We investigated RSK2 effects on integrin function and found that RSK2 mediates H-RAS inactivation of integrins. As a consequence, RSK2 impairs cell adhesion and promotes cell migration. RSK2 co-precipitated with talin and filaminA from -integrin tail complexes, and thereby, we conclude in a position to modulate talin activation of integrins and inactivation by filaminA. RSK2 phosphorylation of filaminA at S2152 enhanced filaminA association with -integrin tails and regulated filaminA- mediated migration. Furthermore, we find that PEA-15 (Phosphoprotein enriched in astrocytes of 15 kDa) is a requirement for efficient recycling of internalized 51 integrins in a manner dependent on RSK2 activity. We propose that RSK2 promotes a highly migratory phenotype as a consequence of filaminA inactivation and subsequent recycling of integrins from the trailing edge of a cell to the advancing leading edge. We also observed that RSK2 promotes invasion and migration in established glioblastoma cell lines U87MG and U373MG and migration in fresh human-derived GBM cells and into cultured mouse brain slices. We present data that indicates inhibition of RSK2 can sensitize GBM cells to chemotherapy treatment with temozolomide. In agreement with our in vitro data, using public datasets, we find that RSK2 expression is significantly upregulated in human GBM patients and correlates with advanced tumor stage and poor prognosis. Taken together, these results reveal RSK2 as a key regulator of integrin activity and provide a novel mechanism by which RSK2 promotes invasion and migration.