PKCepsilon regulation of an alpha5 integrin-ZO-1 complex controls lamellae formation in migrating cancer cells.

Disruption of intercellular adhesions, increased abundance of alpha(5)beta(1) integrin, and activation of protein kinase Cepsilon (PKCepsilon) correlate with invasion and unfavorable prognosis in lung cancer. However, it remains elusive how these distinct factors contribute to the invasive behavior of cancer cells. Persistent cell motility requires the formation of stable lamellae at the leading edge of a migrating cell. Here, we report that the tight junction protein zonula occludens-1 (ZO-1) preferentially interacts with alpha(5)beta(1) integrin at the lamellae of migrating cells. Disruption of ZO-1 binding to an internal PDZ-binding motif in the alpha(5) cytoplasmic tail prevented the polarized localization of ZO-1 and alpha(5) at the leading edge. Furthermore, silencing of alpha(5) integrin inhibited migration and invasion of lung cancer cells, and silencing of ZO-1 resulted in increased Rac activity and reduced directional cell motility. The formation of the alpha(5)-ZO-1 complex was dependent on PKCepsilon: Phosphorylation of ZO-1 at serine-168 regulated the subcellular localization of ZO-1 and thus controlled its association with alpha(5) integrin. In conclusion, PKCepsilon activation drives the formation of a spatially restricted, promigratory alpha(5)-ZO-1 complex at the leading edge of lung cancer cells.

Integrin trafficking regulated by Rab21 is necessary for cytokinesis.

Adherent cells undergo remarkable changes in shape during cell division. However, the functional interplay between cell adhesion turnover and the mitotic machinery is poorly understood. The endo/exocytic trafficking of integrins is regulated by the small GTPase Rab21, which associates with several integrin alpha subunits. Here, we show that targeted trafficking of integrins to and from the cleavage furrow is required for successful cytokinesis, and that this is regulated by Rab21. Rab21 activity, integrin-Rab21 association, and integrin endocytosis are all necessary for normal cytokinesis, which becomes impaired when integrin-mediated adhesion at the cleavage furrow fails. We also describe a chromosomal deletion and loss of Rab21 gene expression in human cancer, which leads to the accumulation of multinucleate cells. Importantly, reintroduction of Rab21 rescued this phenotype. In conclusion, Rab21-regulated integrin trafficking is essential for normal cell division, and its defects may contribute to multinucleation and genomic instability, which are hallmarks of cancer.