p120-Catenin Mediates Inflammatory Responses in the Skin

Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021, USA.
Cell (Impact Factor: 32.24). 02/2006; 124(3):631-44. DOI: 10.1016/j.cell.2005.11.043
Source: PubMed


Although p120-catenin regulates adherens junction (AJ) stability in cultured cells, genetic studies in lower eukaryotes have not revealed a role for this protein in vivo. Using conditional targeting in mice, we show that p120 null neonatal epidermis exhibits reduced intercellular AJ components but no overt disruption in barrier function or intercellular adhesion. As the mice age, however, they display epidermal hyperplasia and chronic inflammation, typified by hair degeneration and loss of body fat. Using skin engraftments and anti-inflammatory drugs, we show that these features are not attributable to reductions in junctional cadherins and catenins, but rather NFkB activation. Both in vivo and in vitro, p120 null epidermal cells activate nuclear NFkB, triggering a cascade of proinflammatory NFkB targets. Although the underlying mechanism is likely complex, we show that p120 affects NFkB activation and immune homeostasis in part through regulation of Rho GTPases. These findings provide important new insights into p120 function.

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Available from: Mirna Perez-Moreno, Mar 17, 2014
    • "Another established consequence of p120 ablation is activation of the RhoA-ROCK-myosin pathway(Dohn et al., 2009; Perez-Moreno et al., 2006; Wildenberg et al., 2006), suggesting a potential role for unbalanced actomyosin contractility. To test whether the presence of collagen alters p120's ability to inhibit this pathway, we blotted for downstream effectors of ROCK in WT, KD and RE cells cultured on collagen. "
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    ABSTRACT: In vertebrate epithelia, p120-catenin mediates E-cadherin stability and suppression of RhoA. Genetic ablation of p120 in various epithelial tissues typically causes striking alterations in tissue function and morphology. Although these effects could very well involve p120's activity towards Rho, ascertaining the impact of this relationship has been complicated by the fact that p120 is also required for cell-cell adhesion. Here, we have molecularly uncoupled p120's cadherin stabilizing- and RhoA-suppressing activity. Unexpectedly, removing p120's Rho-suppressing activity dramatically disrupted the integrity of the apical surface, irrespective of E-cadherin stability. The physical defect was tracked to excessive actomyosin contractility along the vertical axis of lateral membranes. Thus, we suggest that p120's distinct activities toward E-cadherin and Rho are molecularly and functionally coupled, and this in turn enables the maintenance of cell shape in the larger context of an epithelial monolayer. Importantly, local suppression of contractility by cadherin-bound p120 appears to go beyond regulating cell shape, as loss of this activity also leads to major defects in epithelial lumenogenesis.
    No preview · Article · Nov 2015 · Journal of Cell Science
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    • "The biological interplay between p120 catenin and its family members is incompletely understood, especially during development. A number of studies have revealed critical yet diverse roles for p120 catenin in different organ systems (Bartlett et al., 2010; Davis and Reynolds, 2006; Elia et al., 2006; Kurley et al., 2012; Marciano et al., 2011; Oas et al., 2010; Perez-Moreno et al., 2006, 2008; Schackmann et al., 2013; Smalley-Freed et al., 2010; Smalley-Freed et al., 2011; Stairs et al., 2011; Tian et al., 2012). In p120 catenin conditional deletion studies, the results are highly tissue-specific and unpredictable. "
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    ABSTRACT: The intracellular protein p120 catenin aids in maintenance of cell-cell adhesion by regulating E-cadherin stability in epithelial cells. In an effort to understand the biology of p120 catenin in pancreas development, we ablated p120 catenin in mouse pancreatic progenitor cells, which resulted in deletion of p120 catenin in all epithelial lineages of the developing mouse pancreas: islet, acinar, centroacinar, and ductal. Loss of p120 catenin resulted in formation of dilated epithelial tubules, expansion of ductal epithelia, loss of acinar cells, and the induction of pancreatic inflammation. Aberrant branching morphogenesis and tubulogenesis were also observed. Throughout development, the phenotype became more severe, ultimately resulting in an abnormal pancreas comprised primarily of duct-like epithelium expressing early progenitor markers. In pancreatic tissue lacking p120 catenin, overall epithelial architecture remained intact; however, actin cytoskeleton organization was disrupted, an observation associated with increased cytoplasmic PKCζ. Although we observed reduced expression of adherens junction proteins E-cadherin, β-catenin, and α-catenin, p120 catenin family members p0071, ARVCF, and δ-catenin remained present at cell membranes in homozygous p120(f/f) pancreases, potentially providing stability for maintenance of epithelial integrity during development. Adult mice homozygous for deletion of p120 catenin displayed dilated main pancreatic ducts, chronic pancreatitis, acinar to ductal metaplasia (ADM), and mucinous metaplasia that resembles PanIN1a. Taken together, our data demonstrate an essential role for p120 catenin in pancreas development. Copyright © 2014. Published by Elsevier Inc.
    Full-text · Article · Dec 2014 · Developmental Biology
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    • "Rho is a downstream target of GEF-H1 and activates its effector, Rho-kinase, leading to increased phosphorylation of MLC, actomyosin contraction and barrier dysfunction. Rho and Rho kinase my directly stimulate NFkB cascade via yet to be identified mechanisms [14], [28]. Such Rho-dependent stimulation of NFkB cascade leads to increased expression of its downstream targets, the EC inflammation markers ICAM1, VCAM and IL-8 [19], [30], [31]. "
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    ABSTRACT: Acute lung injury (ALI) is accompanied by decreased lung compliance. However, a role of tissue mechanics in modulation of inflammation remains unclear. We hypothesized that bacterial lipopolysacharide (LPS) stimulates extracellular matrix (ECM) production and vascular stiffening leading to stiffness-dependent exacerbation of endothelial cell (EC) inflammatory activation and lung barrier dysfunction. Expression of GEF-H1, ICAM-1, VCAM-1, ECM proteins fibronectin and collagen, lysyl oxidase (LOX) activity, interleukin-8 and activation of Rho signaling were analyzed in lung samples and pulmonary EC grown on soft (1.5 or 2.8 kPa) and stiff (40 kPa) substrates. LPS induced EC inflammatory activation accompanied by expression of ECM proteins, increase in LOX activity, and activation of Rho signaling. These effects were augmented in EC grown on stiff substrate. Stiffness-dependent enhancement of inflammation was associated with increased expression of Rho activator, GEF-H1. Inhibition of ECM crosslinking and stiffening by LOX suppression reduced EC inflammatory activation and GEF-H1 expression in response to LPS. In vivo, LOX inhibition attenuated LPS-induced expression of GEF-H1 and lung dysfunction. These findings present a novel mechanism of stiffness-dependent exacerbation of vascular inflammation and escalation of ALI via stimulation of GEF-H1 - Rho pathway. This pathway represents a fundamental mechanism of positive feedback regulation of inflammation.
    Full-text · Article · Apr 2014 · PLoS ONE
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