Cdc42-dependent formation of the ZO-1/MRCK? complex at the leading edge controls cell migration.

ABSTRACT: Zonula occludens (ZO)-1 is a multi-domain scaffold protein known to have critical roles in the establishment of cell-cell adhesions and the maintenance of stable tissue structures through the targeting, anchoring, and clustering of transmembrane adhesion molecules and cytoskeletal proteins. Here, we report that ZO-1 directly binds to MRCK?, a Cdc42 effector kinase that modulates cell protrusion and migration, at the leading edge of migrating cells. Structural studies reveal that the binding of a ? hairpin from GRINL1A converts ZO-1 ZU5 into a complete ZU5-fold. A similar interaction mode is likely to occur between ZO-1 ZU5 and MRCK?. The interaction between ZO-1 and MRCK? requires the kinase to be primed by Cdc42 due to the closed conformation of the kinase. Formation of the ZO-1/MRCK? complex enriches the kinase at the lamellae of migrating cells. Disruption of the ZO-1/MRCK? complex inhibits MRCK?-mediated cell migration. These results demonstrate that ZO-1, a classical scaffold protein with accepted roles in maintaining cell-cell adhesions in stable tissues, also has an active role in cell migration during processes such as tissue development and remodelling.

SUBMITTER: Huo L 

PROVIDER: S-EPMC3041950 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature