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Vol. 12, Issue 4, 847-862, April 2001
School of Biosciences, University of Birmingham, Edgbaston,
Birmingham B15 2TT, United Kingdom
The establishment of cadherin-dependent cell-cell contacts in
human epidermal keratinocytes are known to be regulated by the Rac1
small GTP-binding protein, although the mechanisms by which Rac1
participates in the assembly or disruption of cell-cell adhesion are
not well understood. In this study we utilized green fluorescent protein (GFP)-tagged Rac1 expression vectors to examine the subcellular distribution of Rac1 and its effects on E-cadherin-mediated cell-cell adhesion. Microinjection of keratinocytes with constitutively active
Rac1 resulted in cell spreading and disruption of cell-cell contacts.
The ability of Rac1 to disrupt cell-cell adhesion was dependent on
colony size, with large established colonies being resistant to the
effects of active Rac1. Disruption of cell-cell contacts in small
preconfluent colonies was achieved through the selective recruitment of
E-cadherin-catenin complexes to the perimeter of multiple large
intracellular vesicles, which were bounded by GFP-tagged L61Rac1.
Similar vesicles were observed in noninjected keratinocytes when
cell-cell adhesion was disrupted by removal of extracellular calcium
or with the use of an E-cadherin blocking antibody. Moreover, formation
of these structures in noninjected keratinocytes was dependent on
endogenous Rac1 activity. Expression of GFP-tagged effector mutants of
Rac1 in keratinocytes demonstrated that reorganization of the actin
cytoskeleton was important for vesicle formation. Characterization of
these Rac1-induced vesicles revealed that they were endosomal in nature
and tightly colocalized with the transferrin receptor, a marker for
recycling endosomes. Expression of GFP-L61Rac1 inhibited uptake of
transferrin-biotin, suggesting that the endocytosis of E-cadherin was a
clathrin-independent mechanism. This was supported by the observation
that caveolin, but not clathrin, localized around these structures.
Furthermore, an inhibitory form of dynamin, known to inhibit
internalization of caveolae, inhibited formation of cadherin vesicles.
Our data suggest that Rac1 regulates adherens junctions via clathrin
independent endocytosis of E-cadherin.
Corresponding author. E-mail address:
n.a.hotchin{at}bham.ac.uk.
*
Present address: School of Biological Sciences, The University
of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
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