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
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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.
    Developmental Biology 12/2014; 399(1). DOI:10.1016/j.ydbio.2014.12.010 · 3.55 Impact Factor
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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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    PLoS ONE 04/2014; 9(4):e92670. DOI:10.1371/journal.pone.0092670 · 3.23 Impact Factor
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    • "A feasible cause of pulmonary inflammation could be reduction in cellular adhesion, as it was described in other systems. Thus, the p120-catenin (a regulator of adherent junctions) conditional mutation in skin triggers a cascade of pro-inflammatory responses that activate ERK1/2 signaling, which finally affects immune homeostasis [109]. In a similar way, loss of Itgb6 in the lung causes emphysema, mediated by TGF-ß activation and an accumulation of lymphocytes and neutrophils [39]. "
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    PLoS ONE 12/2013; 8(12):e83028. DOI:10.1371/journal.pone.0083028 · 3.23 Impact Factor
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