ReviewRegulation of Rho GTPases by p120-catenin
Introduction
p120-catenin is the prototypical member of a subfamily of Armadillo repeat domain proteins involved in intercellular adhesion. It was initially isolated in a screen for Src substrates [1] and subsequently shown to interact with classical cadherins. Recent evidence indicates that p120 regulates cadherin clustering and is necessary for strong cell–cell adhesion, but the underlying mechanisms have not been resolved (for review, see [2•]).
Cadherins comprise a superfamily of transmembrane cell–cell adhesion receptors involved in a variety of biological processes including development, morphogenesis and tumor metastasis (for review, see 3., 4., 5., 6.). Cadherins on adjacent cells bind to one another through their extracellular domains. The intracellular domains anchor the junctional complexes to the actin cytoskeleton through interaction with the catenins. β-catenin binds directly to the carboxy-terminal ‘catenin-binding domain’ (CBD), whereas p120 interacts directly with the so called juxtamembrane domain (JMD) 7., 8•.. β-catenin interacts further with either α-catenin, which hardwires the complex to the actin cytoskeleton 9., 10., 11., or IQGAP, which prevents cytoskeletal association [12]. In contrast, p120 does not bind α-catenin [13] or IQGAP [12]. Thus, unlike β-catenin, the mechanism by which p120 regulates cell–cell adhesion has been less than obvious.
The ability of cadherin complexes to bind α-catenin and associate with the cytoskeleton is promoted by activation of Cdc42 and Rac, which induces IQGAP dissociation from β-catenin and actin polymerization [12]. Indeed, Rho family GTPases (including RhoA, Rac and Cdc42), key mediators of cytoskeletal dynamics [14], have recently emerged as crucial regulators of cadherin-mediated adhesion 15., 16., 17., 18.. Unlike Rac and Cdc42, RhoA activity is thought to be required for an earlier step in junction formation, namely cadherin clustering at sites of cell–cell contact 15., 16..
There is now strong evidence that p120 acts through regulation of Rho GTPases. Independent reports from three laboratories suggest that p120 can inhibit RhoA 19••., 20••. and activate Rac and Cdc42 20••., 21••.. These observations suggest a number of plausible mechanisms through which p120 could promote both cell–cell adhesion and cell motility, depending on factors that direct it to the cadherin complex or the cytoplasm. Here, we review the new evidence and suggest potential roles for the p120–Rho connection in normal and malignant cells.
Section snippets
Positive and negative roles for p120 in regulating cadherin clustering
Experiments focused on the role of p120 in regulating cadherin function suggest that p120 can have both positive and negative effects on adhesion. One line of experimentation involves deleting or mutating the JMD, thereby uncoupling p120 from cadherin function. Cells expressing such JMD mutants are only weakly adherent, apparently due to a defect in cadherin clustering 7., 8•.. As p120 is not directly connected to the actin cytoskeleton, it is likely that these positive effects on clustering
Regulation of Rho GTPases by p120
p120 overexpression in cells typically results in a variety of morphological effects depending on the cell type and the level of p120 overexpression. In fibroblasts, high level overexpression causes a striking ‘branching’ phenotype characterized by extreme arborization of cellular processes [24]. Lesser effects, including increased lamellipodia formation, are observed in most epithelial cell types. The branching phenotype is also observed when p120 is overexpressed in cadherin-deficient cells
Mechanism of action
Despite striking overall agreement, the recent studies discussed above differ in several details that provide substance for the next generation of experiments. A major issue is whether p120 interacts directly with the GTPases or indirectly through the agency of proteins that regulate GTPase function. Exchange assays in vitro suggest that p120 can inhibit the intrinsic GDP/GTP exchange activity of RhoA in a manner comparable to that of the well characterized Rho inhibitor, GDP dissociation
Hypothetical models
p120 and RhoA have been independently implicated in cadherin clustering. Given the observations described herein, it seems unlikely that these activities are unrelated. Interestingly, all three studies argue that cadherin binding and the ability of p120 to affect Rho GTPases are mutually exclusive events. Two models have been proposed to account for the potential importance of these p120 effects in junction formation and cell motility.
The first model attempts to explain the common requirement
A common thread among p120 family members?
Regulation of Rho family GTPases and the actin cytoskeleton could be a trait shared by all p120 family members. Indeed, δ-catenin, a close p120 family member that also associates with the cadherin JMD, increases cell motility upon overexpression [39]. In addition, the Armadillo domain of plakophilin 1, a more distantly related p120 family member, associates with actin filaments [40]. There are now seven armadillo repeat proteins in the p120 subfamily [2•]. All of them appear to have dual
Contact inhibition of cell movement
The data suggest a potentially elegant mechanism for explaining contact inhibition of cell movement. Different cadherins and signaling mechanisms in various cell types could essentially regulate cell movement by controlling the levels of p120 released to the cytoplasm. For example, E cadherin appears to bind p120 more tightly than N cadherin, which is found in motile cells such as fibroblasts. Cell-type-specific p120 isoforms and selective signaling mechanisms may also affect p120 activity
p120 and metastasis
E cadherin expression is frequently downregulated in metastatic carcinomas, an event generally considered to mark the transition to metastasis ([6]; Fig. 3). Under these circumstances, β-catenin is rapidly degraded through its interaction with the tumor suppressor adenomatous polyposis coli (APC). p120 on the other hand, accumulates at high levels in the cytoplasm [8•]. The full ramifications of this condition are not entirely clear. As there is no obvious mechanism for degrading cytoplasmic
Conclusions
The typical view of p120 as a regulator of cadherin function is supported by its ability to switch between active and passive states to regulate junction assembly and disassembly. p120 phosphorylation is thought to regulate the switching between these states, whereas the ability to modulate Rho GTPases could provide the mechanism for dynamic organization at the interface between the cadherin complex and the underlying actin cytoskeleton.
On the other hand, the data reviewed here suggest that
Update
Although earlier reports suggest an important role for Rho family GTPases in adherens junction formation, the mechanism by which these GTPases are activated and targeted to cadherin-mediated junctions is unclear. Three recent reports now demonstrate that cadherin engagement (during a calcium switch experiment) induces the activities of Rac1 and Cdc42 44., 45., 46.. In contrast, cadherin engagement causes a long-term decrease in RhoA activity [46]. Although phosphatidylinositol 3-kinase (PI
Acknowledgements
This work was supported by National Institutes of Health grant CA55724, and by the Vanderbilt Ingram Cancer Center, through the Cancer Center support grant CA69485.
References and recommended reading
Papers of particular interest, published within the annual period of review,have been highlighted as:
•of special interest
••of outstanding interest
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