Activation of the small GTPase Rac is sufficient to disrupt cadherin-dependent cell-cell adhesion in normal human keratinocytes.
To achieve strong adhesion to their neighbors and sustain stress and tension, epithelial cells develop many different specialized adhesive structures. Breakdown of these structures occurs during tumor progression, with the development of a fibroblastic morphology characteristic of metastatic cells. During Ras transformation, Rac-signaling pathways participate in the disruption of cadherin-dependent adhesion. We show that sustained Rac activation per se is sufficient to disassemble cadherin-mediated contacts in keratinocytes, in a concentration- and time-dependent manner. Cadherin receptors are removed from junctions before integrin receptors, suggesting that pathways activated by Rac can specifically interfere with cadherin function. We mapped an important region for disruption of junctions to the putative second effector domain of the Rac protein. Interestingly, although this region overlaps the domain necessary to induce lamellipodia, we demonstrate that the disassembly of cadherin complexes is a new Rac activity, distinct from Rac-dependent lamellipodia formation. Because Rac activity is also necessary for migration, Rac is a good candidate to coordinately regulate cell-cell and cell-substratum adhesion during tumorigenesis.
Braga
V M
VM
Medical Research Council Laboratory for Molecular Cell Biology and the Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, United Kingdom. v.braga@ucl.ac.uk
Betson
M
M
Li
X
X
Lamarche-Vane
N
N
D016475:3T3 Cells / Q000166:cytology; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D048429:Cell Size; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D004789:Enzyme Activation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008845:Microinjections; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D010446:Peptide Fragments; D020744:rac GTP-Binding Proteins