Adhesion dependent regulation of aurora kinase a and its role in rala mediated anchorage independence

Abstract

Integrin mediated adhesion regulates membrane trafficking to control anchorage dependent signaling and growth that is deregulated in cancers Downstream of integrins and oncogenic Ras the small GTPase Ral is a vital mediator of adhesion dependent trafficking and signaling While the role of RalA in these pathways is well established what regulates the small GTPase downstream of integrin and oncogenic Ras is still elusive In this study we find a cell cycle protein Aurora Kinase A AURKA to be an important player that regulates RalA activity downstream of Integrin mediated adhesion We have developed and used a self assembling dextran polymer nanovesicle VMLN to deliver the AURKA inhibitor Alisertib MLN8237 and specifically target AURKA in cells in 2D as well as 3D microenvironments Using this tool to specifically inhibit AURKA we find it regulates integrin dependent RalA activity and cell spreading in early adhesion through the RalGEF RGL1 This could be mediated by the effect AURKA has on RalA and RGL1 localization In anchorage independent cancers the AURKA RalA crosstalk is conserved in Ras independent cancers and remains to be tested in Ras dependent cancers Using VMLN as a tool we have identified two Ras independent cancer cell lines where targeting AURKA specifically inhibits RalA activity and RalA dependent anchorage independent growth Together these studies help identify AURKA as a key regulator of RalA along with adhesion dependent pathways in normal and Ras independent cancers newline newline