Activation of the Small GTPase Rac Is Sufficient to Disrupt Cadherin-dependent Cell-Cell Adhesion in Normal Human Keratinocytes

Medical Research Council Laboratory for Molecular Cell Biology and the Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, United Kingdom.
Molecular Biology of the Cell (Impact Factor: 4.47). 12/2000; 11(11):3703-21. DOI: 10.1091/mbc.11.11.3703
Source: PubMed


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.

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    • "While much is known about how adherens junctions are formed, less is known about the signaling events and molecular interactions that lead to junctional dissociation. Activation of Rac1 and Cdc42 can abolish the multi-cellular organization of breast carcinoma cells in a 3D matrix [20] and disrupts cell–cell adhesions in human keratinocytes [4] and pancreatic carcinoma cells [13]. Moreover, Rac1 and Cdc42 are both known to interact with isoform 1 of the IQ motif containing GTPase activating protein (IQGAP) family of proteins [21], and a Rac-1–IQGAP1 interaction is thought to mediate the dissociation of β-catenin from E-cadherin downstream of HGF in MDCK cells [10]. "
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    • "Cadherins link adherens junctions to the actin cytoskeleton [2]. The small GTPase Rac1 is a key regulator of the epithelial actin cytoskeleton, which influences dynamics of cell-cell contacts [3], [4], [5], [6], [7]. Rac1 is activated upon E-cadherin clustering during de novo cell junction formation and activity decreases as junctions mature [4], [7], [8]. "
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    PLoS ONE 03/2012; 7(3):e31141. DOI:10.1371/journal.pone.0031141 · 3.23 Impact Factor
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    • "Major players functionally connecting classical cadherins to the actin cytoskeleton are the Rho GTPases. Studies using dominant-active and dominant-negative Rho-GTPase mutants demonstrate that aberrant Rho-GTPase signaling in general disrupts cell–cell adhesion, presumably through misregulation of the cytoskeletal organization (Braga et al., 1997, 2000). Conversely, cadherin activity has been shown to affect Rho-GTPase function, with one example being activation of Rac1 by forced cadherin clustering, for which a number of mechanisms have been proposed (Betson et al., 2002; Goodwin et al., 2003; Fukuyama et al., 2006). "
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