Cell Polarity Development and Protein Trafficking in Hepatocytes Lacking E-Cadherin/β-Catenin–based Adherens Junctions

Théard, Delphine; Steiner, Magdalena; Kalicharan, D.; Hoekstra, Dick; IJzendoorn, Sven C. D. van

doi:10.1091/mbc.e06-11-1040

Cited by 61 publications

(56 citation statements)

References 35 publications

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“…Furthermore we also silenced E-cadherin expression in RCC10 cells and observed no effect on TJ assembly (Figure 3). Taken together this implies that disruption of TJs is not dependent on E-cadherin down-regulation in these cells and is consistent with other reports showing that AJ assembly in some other settings is not a prerequisite for TJ formation (Potempa and Ridley, 1998;Chen et al, 2000;Theard et al, 2007). Notably we found that VHL status had a marked effect on expression of occludin and claudin 1, which involved up-regulation at the mRNA level.…”

Section: Discussionsupporting

confidence: 92%

Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin

Harten

Shukla

Barod

et al. 2009

MBoC

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Epithelial-to-mesenchymal transitions (EMT) are important in renal development, fibrosis, and cancer. Loss of function of the tumor suppressor VHL leads to many features of EMT, and it has been hypothesized that the pivotal mediator is down-regulation of the adherens junction (AJ) protein E-cadherin. Here we show that VHL loss-of-function also has striking effects on the expression of the tight junction (TJ) components occludin and claudin 1 in vitro in VHL-defective clear cell renal cell carcinoma (CCRCC) cells and in vivo in VHL-defective sporadic CCRCCs (compared with normal kidney). Occludin is also down-regulated in premalignant foci in kidneys from patients with germline VHL mutations, consistent with a contribution to CCRCC initiation. Reexpression of E-cadherin was sufficient to restore AJ but not TJ assembly, indicating that the TJ defect is independent of E-cadherin down-regulation. Additional experiments show that activation of hypoxia inducible factor (HIF) contributes to both TJ and AJ abnormalities, thus the VHL/HIF pathway contributes to multiple aspects of the EMT phenotype that are not interdependent. Despite the independent nature of the defects, we show that treatment with the histone deacetylase inhibitor sodium butyrate, which suppresses HIF activation, provides a method for reversing EMT in the context of VHL inactivation. INTRODUCTIONA key characteristic of epithelial surfaces is the formation of specialized intercellular junctions at points of cell-cell contact. It is increasingly appreciated that these junctions have extensive roles beyond their function in cellular cohesion including determination of epithelial permeability and providing inputs modulating proliferation and differentiation. Two important types of intercellular junctions in the kidney epithelium are the tight junction (TJ) and adherens junction (AJ; Tsukita et al., 2001;Conacci-Sorrell et al., 2002;Matter and Balda, 2003). AJs are formed on the basolateral cell membrane and are composed of transmembrane cadherins linked to intracellular catenin proteins (Conacci-Sorrell et al., 2002). AJs are involved in cell-cell adhesion and also regulate ␤-catenin availability (Nelson and Nusse, 2004). TJs are formed on the apical surface of the lateral membrane and are analagous in structure to AJs, with specific transmembrane proteins (occludin and claudins), which are linked to the actin cytoskeleton via intracellular adaptor proteins, the zona occludens (ZO) family of proteins (Tsukita et al., 2001). In addition to its traditional roles in maintaining apical-basal polarity and controlling paracellular permeability the TJ is also now recognized as a signaling hub. TJ regulation of pathways involving raf kinase, rho GTPase, and the Y-box transcription factor ZONAB control important cellular processes such as cell proliferation, gene transcription, and cellular differentiation (Braga, 2002;Matter and Balda, 2003;Gonzalez-Mariscal et al., 2007;Guillemot et al., 2008).VHL is a classical tumor suppressor gene which acts as a gatekeeper i...

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Section: Discussionsupporting

confidence: 92%

Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin

Harten

Shukla

Barod

et al. 2009

MBoC

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“…8). Tight junction functionality was not affected by E-cadherin depletion (Capaldo and Macara, 2007;Theard et al, 2007). Thus, we speculate that the inhibition of actomyosin contraction might have two mainly non-exclusive effects.…”

Section: Discussionmentioning

confidence: 80%

ROCK-mediated contractility, tight junctions and channels contribute to the conversion of a preapical patch into apical surface during isochoric lumen initiation

Ferrari

Veligodskiy

Berge

et al. 2008

Journal of Cell Science

110

119

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“…Also, HepG2 cells expressing p27S10A develop full apical-basolateral cell polarity, although with a delay and without subsequent apical lumen remodelling (Théard et al, 2007). It is possible that additional adhesion proteins have compensated for the loss of E-cadherin and ␤-catenin at the cell surface, as was suggested in the conditional E-cadherin knockout mice (Battle et al, 2006).…”

Section: Discussionmentioning

confidence: 92%

Formation of E-Cadherin/β-Catenin–based Adherens Junctions in Hepatocytes Requires Serine-10 in p27(Kip1)

Théard¹,

Raspe²,

Kalicharan

et al. 2008

MBoC

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The adhesion between epithelial cells at adherens junctions is regulated by signaling pathways that mediate the intracellular trafficking and assembly of its core components. Insight into the molecular mechanisms of this is necessary to understand how adherens junctions contribute to the functional organization of epithelial tissues. Here, we demonstrate that in human hepatic HepG2 cells, oncostatin M-p42/44 mitogen-activated protein kinase signaling stimulates the phosphorylation of p27(Kip1) on Ser-10 and promotes cell-cell adhesion. The overexpression of wild-type p27 or a phospho-mimetic p27S10D mutant in HepG2 cells induces a hyper-adhesive phenotype. In contrast, the overexpression of a nonphosphorylatable p27S10A mutant prevents the mobilization of E-cadherin and ␤-catenin at the cell surface, reduces basal cell-cell adhesion strength, and prevents the stimulatory effect of oncostatin M on cell-cell adhesion. As part of the underlying molecular mechanism, it is shown that in p27S10A-expressing cells ␤-catenin interacts with p27 and is prevented from interacting with E-cadherin. The intracellular retention of E-cadherin and ␤-catenin is also observed in hepatocytes from p27S10A knockin mice that express the p27S10A mutant instead of wild-type p27. Together, these data suggest that the formation of adherens junctions in hepatocytes requires Ser-10 in p27.

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Cell Polarity Development and Protein Trafficking in Hepatocytes Lacking E-Cadherin/β-Catenin–based Adherens Junctions

Cited by 61 publications

References 35 publications

Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin

Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin

ROCK-mediated contractility, tight junctions and channels contribute to the conversion of a preapical patch into apical surface during isochoric lumen initiation

Formation of E-Cadherin/β-Catenin–based Adherens Junctions in Hepatocytes Requires Serine-10 in p27(Kip1)

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