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

Lin Huo; Wenyu Wen; Rui Wang; Chuen Kam; Jun Xia; Wei Feng; Mingjie Zhang

doi:10.1038/emboj.2010.353

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.

Authors

Lin Huo¹, Wenyu Wen, Rui Wang, Chuen Kam, Jun Xia, Wei Feng, Mingjie Zhang

Affiliation

¹ Division of Life Science, Molecular Neuroscience Center, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.

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 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*

Substances

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