Par3 integrates Tiam1 and phosphatidylinositol 3-kinase signaling to change apical membrane identity

Ruch, Travis R.; Bryant, David M.; Mostov, Keith E.; Engel, Joanne N.

doi:10.1091/mbc.e16-07-0541

Cited by 11 publications

(6 citation statements)

References 48 publications

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“…Moreover, both the dominant interfering Par3N construct and Par3 depletion reduced the biotinylation of Vangl2 by BL-Pk3, supporting the view that Par3-dependent apical recruitment of Pk3 is essential for PCP complex formation. Whereas the direct binding of Pk3 by Par3 is the simplest interpretation of our data, alternatively, Par3 may recruit Pk3 to the apical domain by altering apical membrane properties ( Ahmed and Macara, 2017 ; Bryant et al, 2010 ; Ruch et al, 2017 ). It is currently unknown whether the Par3/Pk3 interaction is modulated by other Par3-associated proteins, such as Par6, JAM-A or Nectin ( Ebnet et al, 2001 ; Joberty et al, 2000 ; Takekuni et al, 2003 ).…”

Section: Discussionmentioning

confidence: 77%

Par3 interacts with Prickle3 to generate apical PCP complexes in the vertebrate neural plate

Chuykin

Ossipova

Sokol

2018

eLife

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Vertebrate neural tube formation depends on the coordinated orientation of cells in the tissue known as planar cell polarity (PCP). In the Xenopus neural plate, PCP is marked by the enrichment of the conserved proteins Prickle3 and Vangl2 at anterior cell boundaries. Here we show that the apical determinant Par3 is also planar polarized in the neuroepithelium, suggesting a role for Par3 in PCP. Consistent with this hypothesis, interference with Par3 activity inhibited asymmetric distribution of PCP junctional complexes and caused neural tube defects. Importantly, Par3 physically associated with Prickle3 and promoted its apical localization, whereas overexpression of a Prickle3-binding Par3 fragment disrupted PCP in the neural plate. We also adapted proximity biotinylation assay for use in Xenopus embryos and show that Par3 functions by enhancing the formation of the anterior apical PCP complex. These findings describe a mechanistic link between the apical localization of PCP components and morphogenetic movements underlying neurulation.

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Section: Discussionmentioning

confidence: 77%

Par3 interacts with Prickle3 to generate apical PCP complexes in the vertebrate neural plate

Chuykin

Ossipova

Sokol

2018

eLife

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“…S5D, and Movies S3 and S4). Delocalization of basolateral and tight-junctional proteins is one of the first steps that leads to the loss of cell polarity (39). Accordingly, epithelial cells of organoids infected with H. pylori show an increased cytoplasmic and apical distribution of the basolateral protein Scribble (Fig.…”

Section: Resultsmentioning

confidence: 99%

CagA–ASPP2 complex mediates loss of cell polarity and favors H. pylori colonization of human gastric organoids

Buti

Ruiz‐Puig

Sangberg

et al. 2020

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

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The main risk factor for stomach cancer, the third most common cause of cancer death worldwide, is infection with Helicobacter pylori bacterial strains that inject cytotoxin-associated gene A (CagA). As the first described bacterial oncoprotein, CagA causes gastric epithelial cell transformation by promoting an epithelial-to-mesenchymal transition (EMT)-like phenotype that disrupts junctions and enhances motility and invasiveness of the infected cells. However, the mechanism by which CagA disrupts gastric epithelial cell polarity to achieve its oncogenicity is not fully understood. Here we found that the apoptosis-stimulating protein of p53 2 (ASPP2), a host tumor suppressor and an important CagA target, contributes to the survival of cagA-positive H. pylori in the lumen of infected gastric organoids. Mechanistically, the CagA–ASPP2 interaction is a key event that promotes remodeling of the partitioning-defective (PAR) polarity complex and leads to loss of cell polarity of infected cells. Blockade of cagA-positive H. pylori ASPP2 signaling by inhibitors of the EGFR (epidermal growth factor receptor) signaling pathway—identified by a high-content imaging screen—or by a CagA-binding ASPP2 peptide, prevents the loss of cell polarity and decreases the survival of H. pylori in infected organoids. These findings suggest that maintaining the host cell-polarity barrier would reduce the detrimental consequences of infection by pathogenic bacteria, such as H. pylori, that exploit the epithelial mucosal surface to colonize the host environment.

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“…In fact, all polarity proteins can act as tumor promoters or suppressors, and are intimately linked to signaling cascades that control cell growth and proliferation, including the HIPPO and TGFß pathways [8][9][10]. In addition, the polarity proteins are required for the biogenesis of the primary cilium [11,12], they control polarized membrane transport, for instance, via the exocyst complex [13], they establish phospholipid polarity [14][15][16], and they orchestrate asymmetric cell division and mitotic spindle positioning [17][18][19][20][21]. Hence, the polarity proteins control epithelial polarity and morphogenesis by integrating various cellular processes.…”

Section: Introductionmentioning

confidence: 99%

New insights into the organization and regulation of the apical polarity network in mammalian epithelial cells

et al. 2021

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Cell polarity is a fundamental property of most animal cells and is critical during development and for most cell and tissue functions. Epithelial cells are organized into apical and basolateral compartments, and this intrinsic cellular asymmetry is essential for all functions that are carried out by epithelial tissue. The establishment of a polarized epithelial phenotype is orchestrated by major rearrangements of the cell cytoskeleton, polarized membrane trafficking, the formation and maturation of epithelial cell junctions, cell signaling pathways, and the generation of cortical phospholipid asymmetry. These processes need to be coordinated precisely in time and space and integrated with physical and chemical signals from the environment, failure of which leads to severe developmental disorders and various human diseases. At the heart of this regulatory network are the evolutionarily conserved polarity modules Par, Crumbs, and Scribble, whose components engage in complex cooperative and antagonistic interactions to compartmentalize and functionalize the epithelial cell cortex and to control the spatiotemporal activity of downstream polarity effectors. In this review, we will discuss recent insights into the organization and regulation of the mammalian Par and Crumbs modules and outline a hypothetical framework of how these proteins orchestrate epithelial polarity development, HIPPO signaling, and actomyosin activity at the apical–lateral border.

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Par3 integrates Tiam1 and phosphatidylinositol 3-kinase signaling to change apical membrane identity

Abstract: The polarity regulator Par3 directs the reorganization of the apical membrane in polarized cells through the action of phosphatidylinositol 3-kinase and the Rac1 exchange factor Tiam1. This mechanism may be exploited by pathogens to bypass the epithelial barrier.

Cited by 11 publications

References 48 publications

Par3 interacts with Prickle3 to generate apical PCP complexes in the vertebrate neural plate

Par3 interacts with Prickle3 to generate apical PCP complexes in the vertebrate neural plate

CagA–ASPP2 complex mediates loss of cell polarity and favors H. pylori colonization of human gastric organoids

New insights into the organization and regulation of the apical polarity network in mammalian epithelial cells

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