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Vol. 11, Issue 11, 3703-3721, November 2000
and
*Medical Research Council Laboratory for Molecular Cell
Biology and the Department of Biochemistry and Molecular Biology,
University College London, London WC1E 6BT, United Kingdom; and
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.
Department of Anatomy and Cell Biology, McGill
University, Montreal, Canada H3A 2B2
Corresponding author. E-mail address:
v.braga{at}ucl.ac.uk.
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