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Par-3 family proteins in cell polarity & adhesion.

ABSTRACT: The Par-3/Baz family of polarity determinants is highly conserved across metazoans and includes C. elegans PAR-3, Drosophila Bazooka (Baz), human Par-3 (PARD3), and human Par-3-like (PARD3B). The C. elegans PAR-3 protein localises to the anterior pole of asymmetrically dividing zygotes with cell division cycle 42 (CDC42), atypical protein kinase C (aPKC), and PAR-6. The same C. elegans 'PAR complex' can also localise in an apical ring in epithelial cells. Drosophila Baz localises to the apical pole of asymmetrically dividing neuroblasts with Cdc42-aPKC-Par6, while in epithelial cells localises both in an apical ring with Cdc42-aPKC-Par6 and with E-cadherin at adherens junctions. These apical and junctional localisations have become separated in human PARD3, which is strictly apical in many epithelia, and human PARD3B, which is strictly junctional in many epithelia. We discuss the molecular basis for this fundamental difference in localisation, as well as the possible functions of Par-3/Baz family proteins as oligomeric clustering agents at the apical domain or at adherens junctions in epithelial stem cells. The evolution of Par-3 family proteins into distinct apical PARD3 and junctional PARD3B orthologs coincides with the emergence of stratified squamous epithelia in vertebrates, where PARD3B, but not PARD3, is strongly expressed in basal layer stem cells - which lack a typical apical domain. We speculate that PARD3B may contribute to clustering of E-cadherin, signalling from adherens junctions via Src family kinases or mitotic spindle orientation by adherens junctions in response to mechanical forces.

SUBMITTER: Thompson BJ

PROVIDER: S-EPMC9290619 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Cortical PAR polarity proteins promote robust cytokinesis during asymmetric cell division.

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The microRNA-200 family mediates hair follicle development through coordinated regulation of cell adhesion and polarity

Project description:The microRNA-200 family is highly expressed in epithelial cells and frequently lost in metastatic cancer. Although the tumor-suppressing roles of this family are well documented and directly linked to the inhibition of mesenchymal genes, their targets and functions in normal epithelial tissues remain unclear. Furthermore, how the two sub-families of the five-microRNA family distinguished by a single nucleotide within the seed region regulate their targets is unclear. Here we show that the microRNA-200 family governs hair morphogenesis and fine-tunes stem cell specification by regulating cell adhesion, polarity and signaling pathways. By directly ligating microRNAs to their targeted mRNA regions, we identify numerous targets involved in the regulation of actin cytoskeleton, focal adhesion, cell cycle and Hippo/Yap signaling in a miRNA:mRNA pair-specific manner. The two sub-families bind to largely distinct target sites although many genes are regulated by both sub-families for a greater degree of regulation. Using inducible and knockout mouse models, we show that the microRNA-200 family enhances cell adhesion, inhibits migration and reduces cell division, contributing to precise stem cell specification. Our findings demonstrate that combinatorial targeting of many genes is critical for microRNA functions and provide new insights into microRNA-200s’ functions in normal epithelial tissues.

2018-03-16 | GSE102291 | GEO

aPKC Cycles between Functionally Distinct PAR Protein Assemblies to Drive Cell Polarity.

Project description:The conserved polarity effector proteins PAR-3, PAR-6, CDC-42, and atypical protein kinase C (aPKC) form a core unit of the PAR protein network, which plays a central role in polarizing a broad range of animal cell types. To functionally polarize cells, these proteins must activate aPKC within a spatially defined membrane domain on one side of the cell in response to symmetry-breaking cues. Using the Caenorhabditis elegans zygote as a model, we find that the localization and activation of aPKC involve distinct, specialized aPKC-containing assemblies: a PAR-3-dependent assembly that responds to polarity cues and promotes efficient segregation of aPKC toward the anterior but holds aPKC in an inactive state, and a CDC-42-dependent assembly in which aPKC is active but poorly segregated. Cycling of aPKC between these distinct functional assemblies, which appears to depend on aPKC activity, effectively links cue-sensing and effector roles within the PAR network to ensure robust establishment of polarity.

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Stabilization of cell polarity by the C. elegans RING protein PAR-2.

Project description:Asymmetric localization of PAR proteins is a hallmark of polarized cells, but the mechanisms that create PAR asymmetry are not well understood. In the C. elegans zygote, PAR asymmetry is initiated by a transient actomyosin contraction, which sweeps the PAR-3/PAR-6/PKC-3 complex toward the anterior pole of the egg. The RING finger protein PAR-2 accumulates in a complementary pattern in the posterior cortex. Here we present evidence that PAR-2 participates in a feedback loop to stabilize polarity. PAR-2 is a target of the PKC-3 kinase and is excluded from the anterior cortex by PKC-3-dependent phosphorylation. The RING domain of PAR-2 is required to overcome inhibition by PKC-3 and stabilize PAR-2 on the posterior cortex. Cortical PAR-2 in turn prevents PAR-3/PAR-6/PKC-3 from returning to the posterior, in a PAR-1- and PAR-5-dependent manner. Our findings suggest that reciprocal inhibitory interactions among PAR proteins stabilize polarity by reinforcing an initial asymmetry in PKC-3.

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Cell polarity triggered by cell-cell adhesion via E-cadherin.

Project description:Cell polarity is orchestrated by numerous extracellular cues, and guides events such as chemotaxis, mitosis and wound healing. In scrape-wound assays of cell monolayers, wound-edge cells orient their centrosomes towards the wound, a process that appears to depend on the formation of new cell-extracellular-matrix adhesions as cells spread into the wound. In direct contrast to scrape-wounded cells, isolated cells without cell-cell contacts failed to polarize, suggesting that asymmetry of cell-cell adhesions resulting from monolayer disruption might contribute to polarization. By using micropatterned substrates to engineer such asymmetries in kidney epithelial cells, we found that cell-cell contact induced displacement of the nucleus towards the contact, and also caused centrosomal reorientation and lamellipodial ruffling to the distal side of the nucleus. Upon release from micropatterned constraints, cells exhibited directed migration away from the cell-cell contact. Disrupting E-cadherin engagement randomized nuclear position and lamellipodial ruffling in patterned cultures, and abrogated scrape-wound-induced cell reorientation, but not migration rate. Polarity that was induced by cell-cell contact required an intact actin cytoskeleton and Cdc42 activity, but not RhoA or Rac signaling. Together, these findings demonstrate a novel role for cell-cell adhesion in polarization, and have implications for wound healing and developmental patterning.

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PAR-3 mediates the initial clustering and apical localization of junction and polarity proteins during C. elegans intestinal epithelial cell polarization.

Project description:The apicobasal polarity of epithelial cells is critical for organ morphogenesis and function, and loss of polarity can promote tumorigenesis. Most epithelial cells form when precursor cells receive a polarization cue, develop distinct apical and basolateral domains and assemble junctions near their apical surface. The scaffolding protein PAR-3 regulates epithelial cell polarity, but its cellular role in the transition from precursor cell to polarized epithelial cell has not been determined in vivo. Here, we use a targeted protein-degradation strategy to remove PAR-3 from C. elegans embryos and examine its cellular role as intestinal precursor cells become polarized epithelial cells. At initial stages of polarization, PAR-3 accumulates in cortical foci that contain E-cadherin, other adherens junction proteins, and the polarity proteins PAR-6 and PKC-3. Using live imaging, we show that PAR-3 foci move apically and cluster, and that PAR-3 is required to assemble E-cadherin into foci and for foci to accumulate at the apical surface. We propose that PAR-3 facilitates polarization by promoting the initial clustering of junction and polarity proteins that then travel and accumulate apically. Unexpectedly, superficial epidermal cells form apical junctions in the absence of PAR-3, and we show that PAR-6 has a PAR-3-independent role in these cells to promote apical junction maturation. These findings indicate that PAR-3 and PAR-6 function sequentially to position and mature apical junctions, and that the requirement for PAR-3 can vary in different types of epithelial cells.

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