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

EMBO J. 2011 Feb 16;30(4):665-78. doi: 10.1038/emboj.2010.353. Epub 2011 Jan 14.


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 MRCKβ, 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 β 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 MRCKβ. The interaction between ZO-1 and MRCKβ requires the kinase to be primed by Cdc42 due to the closed conformation of the kinase. Formation of the ZO-1/MRCKβ complex enriches the kinase at the lamellae of migrating cells. Disruption of the ZO-1/MRCKβ complex inhibits MRCKβ-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Cell Adhesion / genetics
  • Cell Adhesion / physiology
  • Cell Compartmentation / physiology
  • Cell Movement* / genetics
  • Cell Movement* / physiology
  • Cells, Cultured
  • Chlorocebus aethiops
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Myotonin-Protein Kinase
  • Phosphoproteins / chemistry
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Binding / genetics
  • Protein Binding / physiology
  • Protein Structure, Secondary
  • Protein Transport / genetics
  • Protein Transport / physiology
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Sequence Homology, Amino Acid
  • Transfection
  • Zonula Occludens-1 Protein
  • cdc42 GTP-Binding Protein / chemistry
  • cdc42 GTP-Binding Protein / genetics
  • cdc42 GTP-Binding Protein / metabolism
  • cdc42 GTP-Binding Protein / physiology*


  • Membrane Proteins
  • Multiprotein Complexes
  • Phosphoproteins
  • TJP1 protein, human
  • Zonula Occludens-1 Protein
  • CDC42BPB protein, human
  • Protein-Tyrosine Kinases
  • Myotonin-Protein Kinase
  • cdc42 GTP-Binding Protein