ZO-2-DEPENDENT STABILIZATION OF LATS1 FOR YAP NUCLEAR EXCLUSION DURING APICAL-BASAL CELL POLARIZATION

Abstract

It is known that physical forces between cells can regulate organ size through inhibition of cell divisions. Intercellular compaction activates the Hippo cascade, which involves several kinases to phosphorylate a transcriptional co-activator YAP to promote its cytoplasmic retention. Although recent research suggests apical-basal cell polarity can indirectly inactivate YAP through Hippo signaling and LATS1 activity, it is not clear whether cell polarity could influence ZO-2 to regulate YAP nuclear exclusion. This project finds that apical-basal cell polarization, rather than physical compaction of cells, dictates ZO-2 to scaffold LATS1-YAP interaction at the apical junctions to promote YAP phosphorylation and cytoplasmic retention. Furthermore, ZO-2 also acts to protect LATS1 from ubiquitin-dependent proteasome degradation. Thus, ZO-2 mediates cell contact inhibition by linking the maturation of cell-cell junctions to promoting LATS1 to phosphorylate YAP outside the nucleus. These findings provide important insights into the regulation of cellular contact inhibition for organ size control.