Differential roles of cyclin-CDK1 complexes in cell migration and invasion

Abstract

Two key hallmarks of cancer are dysregulated proliferation and metastasis, which are co- ordinated at the single cell level by regulation of cell-cycle progression and invasive cell migration respectively. We have previously described a central role for CDK1 at the nexus of adhesion signalling and cell cycle progression, demonstrating that CDK1 has a non-canonical role in regulating integrin adhesion complexes and in the migration of cancer cells in 3D interstitial matrix. Here we show that the CDK1 binding partners cyclinB1 and cyclinA2 also have roles in cell migration and invasion in both cancer and non-transformed cells. CyclinB1 plays a key role in RhoA activation to promote rear retraction in a membrane tension dependent manner, while cyclinA2 has a general role in promoting motility. Knockdown of either cyclin significantly perturbs migration with contrasting phenotypes, while knockdown of both together has an additive effect which arrests both migration and division. We find that the cell migration specific role of CDK1 is independent of cell-cycle phase, with inhibition or knockdown of CDK1 perturbing migration in G0/G1 arrested cells, while CDK1-cyclin expression correlates strongly with invasive potential of bladder cancer cell lines. Our findings therefore describe how cyclin-CDK1 complexes orchestrate migration as well as division of cells and that cyclinA2-CDK1 and cyclinB1-CDK1 complexes play distinct roles in motility. Furthermore, these findings suggest that targeting CDK1 signalling in aggressive and invasive tumours may have an unexpected dual potential to combat metastasis in addition to proliferation.