Cdc42-dependent formation of the ZO-1/MRCKβ complex at the leading edge controls cell migration.
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.
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.
Lin
L
Huo
Wenyu
W
Wen
Rui
R
Wang
Chuen
C
Kam
Jun
J
Xia
Wei
W
Feng
Mingjie
M
Zhang
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002451:Cell Compartmentation / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D065636:Myotonin-Protein Kinase; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D017433:Protein Structure, Secondary; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D062826:Zonula Occludens-1 Protein; D020764:cdc42 GTP-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D008565:Membrane Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; C118666:CDC42BPB protein, human; D011505:Protein-Tyrosine Kinases; D065636:Myotonin-Protein Kinase; D020764:cdc42 GTP-Binding Protein
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