P120 Catenin Regulates the Actin Cytoskeleton via Rho Family Gtpases

By Nicole K. Noren, Betty P. Liu, K. Burridge, B. Kreft. Journal of Cell Biology, 2000

597 citations recorded by the source corpus.

Cadherins are calcium-dependent adhesion molecules responsible for the establishment of tight cell–cell contacts. p120 catenin (p120ctn) binds to the cytoplasmic domain of cadherins in the juxtamembrane region, which has been implicated in regulating cell motility. It has previously been shown that overexpression of p120ctn induces a dendritic morphology in fibroblasts (Reynolds, A.B., J. Daniel, Y. Mo, J. Wu, and Z. Zhang. 1996. Exp. Cell Res. 225:328–337.). We show here that this phenotype is suppressed by coexpression of cadherin constructs that contain the juxtamembrane region, but not by constructs lacking this domain. Overexpression of p120ctn disrupts stress fibers and focal adhesions and results in a decrease in RhoA activity. The p120ctn-induced phenotype is blocked by dominant negative Cdc42 and Rac1 and by constitutively active Rho-kinase, but is enhanced by dominant negative RhoA. p120ctn overexpression increased the activity of endogenous Cdc42 and Rac1. Exploring how p120ctn may regulate Rho family GTPases, we find that p120ctn binds the Rho family exchange factor Vav2. The behavior of p120ctn suggests that it is a vehicle for cross-talk between cell–cell junctions and the motile machinery of cells. We propose a model in which p120ctn can shuttle between a cadherin-bound state and a cytoplasmic pool in which it can interact with regulators of Rho family GTPases. Factors that perturb cell–cell junctions, such that the cytoplasmic pool of p120ctn is increased, are predicted to decrease RhoA activity but to elevate active Rac1 and Cdc42, thereby promoting cell migration.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/30345d78a6c23de2cdaad32eacab6e74c4591901

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Citations in the corpus

A core function for p120-catenin in cadherin turnover (2003, background): “…and may also regulate cadherin–cytoskeletal connections indirectly through functional interactions with Rho GTPases (Anastasiadis et al., 2000; Noren et al., 2000; Grosheva et al., 2001; Magie et al., 2002; for review see Anastasiadis and Reynolds, 2001), but the underlying mechanisms have…”
EMT, the cytoskeleton, and cancer cell invasion (2009, background): “Furthermore, p120-catenin plays an elementary role in the stability of epithelial cell-cell adhesion by repressing the activity of RhoA and activating Rac and Cdc42 [31–33].”
Helicobacter pylori and Gastric Cancer: Factors That Modulate Disease Risk (2010, background): “Loss of E-cadherin or overexpression of p120 in vitro results in mislocalization of p120 to the cytoplasm (258), where it can promote motility and metastasis via interactions between p120 and Rho GTPases (14, 120, 223).”
Role of tissue stroma in cancer cell invasion (2003, background): “P120ctn may influence the activity of Rho family GTPases, thereby influencing motility and invasion [189,190].”
Cell adhesion and signalling by cadherins and Ig-CAMs in cancer (2004, background): “On the other hand, recent studies indicate that p120-catenin promotes cell migration by recruiting and activating RAC1 and CDC42, probably through the GEF VAV2, and by inhibiting RHO”
Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. (2006, unknown): “p120 may regulate the cadherin–actin cytoskeleton nexus directly by binding and inhibiting RhoA (Anastasiadis and Reynolds 2001) and indirectly activating Rac1 and Cdc42 via Vav2 (Noren et al. 2000), while stabilizing cadherins at the cell surface (Davis et al.”
Endothelial cell–cell junctions: happy together (2004, background): “Important effectors of the EMT are RHO-FAMILY GTPASES”
Cdc42 - the centre of polarity (2004, background): “Multiple Cdc42 targets mediate polarization Cdc42 regulates the actin cytoskeleton One of the best-characterized targets of Cdc42 and Rac is the p65PAK family of serine/threonine kinases (reviewed by Bokoch, 2003). p65PAK associates with F-actin in membrane ruffles and lamellipodia at the leading ed”
Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. (2002, background): “Overexpression of this protein can lead to decreased RhoA activity, increased Rac and CDC42 activity, and dramatic changes in cell morphology (32).”