Binding between the Junctional Proteins Afadin and PLEKHA7 and Implication in the Formation of Adherens Junction in Epithelial Cells

Kurita, Souichi; Yamada, Tomohiro; Rikitsu, Etsuko; Ikeda, Wataru; Takai, Yoshimi

doi:10.1074/jbc.m113.453464

Cited by 54 publications

(65 citation statements)

References 42 publications

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“…3248 Therefore, migration of PTPRZ1-expressing liver cells is likely to be impacted by PTN-dependent phosphorylation of these proteins. Evidence that PTN-PTPRZ1 signaling modulates phosphorylation of afadin in liver cells is also relevant because afadin is a key component of adherens junctions 4950 and phosphorylation results in afadin translocation from adherens junctions into the nucleus. 51 This translocation step is regulated by PI3K/Akt, the latter being activated by PTN/PTPRZ1 signaling.…”

Section: Discussionmentioning

confidence: 99%

Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches

Michelotti

Tucker

Swiderska‐Syn

et al. 2015

Gut

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ObjectiveThe ductular reaction (DR) involves mobilisation of reactive-appearing duct-like cells (RDC) along canals of Hering, and myofibroblastic (MF) differentiation of hepatic stellate cells (HSC) in the space of Disse. Perivascular cells in stem cell niches produce pleiotrophin (PTN) to inactivate the PTN receptor, protein tyrosine phosphatase receptor zeta-1 (PTPRZ1), thereby augmenting phosphoprotein-dependent signalling. We hypothesised that the DR is regulated by PTN/PTPRZ1 signalling.DesignPTN-GFP, PTN-knockout (KO), PTPRZ1-KO, and wild type (WT) mice were examined before and after bile duct ligation (BDL) for PTN, PTPRZ1 and the DR. RDC and HSC from WT, PTN-KO, and PTPRZ1-KO mice were also treated with PTN to determine effects on downstream signaling phosphoproteins, gene expression, growth, and migration. Liver biopsies from patients with DRs were also interrogated.ResultsAlthough quiescent HSC and RDC lines expressed PTN and PTPRZ1 mRNAs, neither PTN nor PTPRZ1 protein was demonstrated in healthy liver. BDL induced PTN in MF-HSC and increased PTPRZ1 in MF-HSC and RDC. In WT mice, BDL triggered a DR characterised by periportal accumulation of collagen, RDC and MF-HSC. All aspects of this DR were increased in PTN-KO mice and suppressed in PTPRZ1-KO mice. In vitro studies revealed PTN-dependent accumulation of phosphoproteins that control cell-cell adhesion and migration, with resultant inhibition of cell migration. PTPRZ1-positive cells were prominent in the DRs of patients with ductal plate defects and adult cholestatic diseases.ConclusionsPTN, and its receptor, PTPRZ1, regulate the DR to liver injury by controlling the migration of resident cells in adult liver progenitor niches.

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Section: Discussionmentioning

confidence: 99%

Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches

Michelotti

Tucker

Swiderska‐Syn

et al. 2015

Gut

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“…PLEKHA7 localizes to the zonula adhaerens belt of the apical-junctional complex in epithelial cells, where it directly interacts with p120 catenin, paracingulin, and afadin (24,(28)(29)(30)(31). Unlike E-cadherin or p120 catenin, PLEKHA7 is not required for adherens junctions formation, and previous studies suggest a role for PLEKHA7 in regulating the stability of the adherens junctions (24,(28)(29)(30)(31). In accord with adherens junctions mediating α-toxin injury, our screen also identified several other junctional components including α-catenin, afadin, and Fig.…”

Section: Resultsmentioning

confidence: 99%

The adherens junctions control susceptibility to Staphylococcus aureus α-toxin

Popov

Marceau

Starkl

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Staphylococcus aureus is both a transient skin colonizer and a formidable human pathogen, ranking among the leading causes of skin and soft tissue infections as well as severe pneumonia. The secreted bacterial α-toxin is essential for S. aureus virulence in these epithelial diseases. To discover host cellular factors required for α-toxin cytotoxicity, we conducted a genetic screen using mutagenized haploid human cells. Our screen identified a cytoplasmic member of the adherens junctions, plekstrin-homology domain containing protein 7 (PLEKHA7), as the second most significantly enriched gene after the known α-toxin receptor, a disintegrin and metalloprotease 10 (ADAM10). Here we report a new, unexpected role for PLEKHA7 and several components of cellular adherens junctions in controlling susceptibility to S. aureus α-toxin. We find that despite being injured by α-toxin pore formation, PLEKHA7 knockout cells recover after intoxication. By infecting PLEKHA7 −/− mice with methicillin-resistant S. aureus USA300 LAC strain, we demonstrate that this junctional protein controls disease severity in both skin infection and lethal S. aureus pneumonia. Our results suggest that adherens junctions actively control cellular responses to a potent pore-forming bacterial toxin and identify PLEKHA7 as a potential nonessential host target to reduce S. aureus virulence during epithelial infections.Staphylococcus aureus | α-toxin | adherens junctions | MRSA | PLEKHA7

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“…Taken together, these results suggest that Cdc42 and afadin act in a similar pathway to promote polarization and lumen formation. Based on in vitro data from others (Kawakatsu et al, 2002;Kurita et al, 2013;Mandai et al, 2013;Nakanishi and Takai, 2004), we speculate that afadin acts upstream of Cdc42 in the signaling pathway; however, this still needs to be verified. We used Cdc42 −/− collecting duct cells to demonstrate that Cdc42 is required for in vitro 3D tubulogenesis as well as collecting duct cell adhesion, migration and proliferation on all extracellular matrices.…”

Section: Discussionmentioning

confidence: 99%

“…At the molecular level, absence of afadin in developing nephrons results in a delayed lumen formation and a reduced ability to correctly localize members of the Par complex (Par3-Par6-aPKCCdc42; in mammals, Par3 is also known as PARD3 and Par6 as PARD6, with each having two isoforms) to the forming epithelia, suggesting that defects in Par complex function and Cdc42 activation might be the underlying defect. Afadin is necessary for Cdc42 activation in vitro (Kawakatsu et al, 2002;Kurita et al, 2013;Mandai et al, 2013;Nakanishi and Takai, 2004), suggesting that the principal mechanisms whereby Cdc42 regulates tubulogenesis in the kidney might be by altering the actin cytoskeleton and apical-basal polarity of the epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Cdc42 regulates epithelial cell polarity and cytoskeletal function in kidney tubule development

Elias

Das

Parekh

et al. 2015

Journal of Cell Science

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The Rho GTPase Cdc42 regulates key signaling pathways required for multiple cell functions, including maintenance of shape, polarity, proliferation, migration, differentiation and morphogenesis. Although previous studies have shown that Cdc42 is required for proper epithelial development and maintenance, its exact molecular function in kidney development is not well understood. In this study, we define the specific role of Cdc42 during murine kidney epithelial tubulogenesis by deleting it selectively at the initiation of ureteric bud or metanephric mesenchyme development. Deletion in either lineage results in abnormal tubulogenesis, with profound defects in polarity, lumen formation and the actin cytoskeleton. Ultimately, these defects lead to renal failure. Additionally, in vitro analysis of Cdc42-null collecting duct cells shows that Cdc42 controls these processes by regulating the polarity Par complex (Par3-Par6-aPKC-Cdc42) and the cytoskeletal proteins N-Wasp and ezrin. Thus, we conclude that the principal role of Cdc42 in ureteric bud and metanephric mesenchyme development is to regulate epithelial cell polarity and the actin cytoskeleton.

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Binding between the Junctional Proteins Afadin and PLEKHA7 and Implication in the Formation of Adherens Junction in Epithelial Cells

Cited by 54 publications

References 42 publications

Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches

Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches

The adherens junctions control susceptibility to Staphylococcus aureus α-toxin

Cdc42 regulates epithelial cell polarity and cytoskeletal function in kidney tubule development

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