Establishment of the PAR-1 cortical gradient by the aPKC-PRBH circuit

Ramanujam, Ravikrishna; Han, Ziyin; Zhang, Zhen; Kanchanawong, Pakorn; Motegi, Fumio

doi:10.1038/s41589-018-0117-1

Cited by 22 publications

(34 citation statements)

References 55 publications

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“…By analogy, binding with Scrib and/or Dlg could allosterically regulate Lgl to prevent phosphorylation, although we have ruled out Lgl-Scrib and Lgl-Dlg interactions documented in the literature (34,66). Scrib or Dlg might also act as a "decoy substrate" for aPKC, as PAR-2 does in PAR-1 protection (63). Indeed, Scrib is phosphorylated on at least 13 residues in Drosophila embryos, though the functional relevance of this is not yet known (67).…”

Section: Discussionmentioning

confidence: 98%

Distinct activities of Scrib module proteins organize epithelial polarity

Khoury

Bilder

2019

Preprint

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A polarized architecture is central to both epithelial structure and function. In many cells, polarity involves mutual antagonism between the Par complex and the Scrib module. While molecular mechanisms underlying Par-mediated apical determination are well-understood, how Scrib module proteins specify the basolateral domain remains unknown. Here, we demonstrate dependent and independent activities of Scrib, Dlg and Lgl using the Drosophila follicle epithelium. Our data support a linear hierarchy for localization, but rule out previously proposed protein-protein interactions as essential for polarization. Membrane recruitment of Scrib does not require palmitoylation or polar phospholipid binding but instead an independent cortically-stabilizing activity of Dlg. Scrib and Dlg do not directly antagonize aPKC, but may instead restrict aPKC localization by enabling the aPKC-inhibiting activity of Lgl. Importantly, while Scrib, Dlg and Lgl are each required, all three together are not sufficient to antagonize the Par complex. Our data demonstrate previously unappreciated diversity of function within the Scrib module and begin to define the elusive molecular functions of Scrib and Dlg. SIGNIFICANCE STATEMENTTo enable their physiological functions, cells must polarize their plasma membrane. In many epithelia, polarity is regulated by balanced activity of the apical Par complex and basolateral Scribble module. While the former is understood in molecular detail, little is known about how the latter works. We identify distinct functions of the three Scribble module proteins, separating independent roles in a localization hierarchy from cooperative roles in apical polarity antagonism and showing that they are not together sufficient to specify basolateral identity. This work establishes an essential basis for a mechanistic understanding of this core polarity machinery that controls processes ranging from stem cell divisions to organ morphogenesis across animal species.

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Section: Discussionmentioning

confidence: 98%

Distinct activities of Scrib module proteins organize epithelial polarity

Khoury

Bilder

2019

Preprint

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“…LGL-1/Lgl and PAR-1. Both proteins are direct aPKC targets in epithelia, and in the C. elegans zygote their anterior exclusion is mediated by PKC-3 (Beatty et al, 2010;Betschinger et al, 2003;Doerflinger et al, 2010;Hoege et al, 2010;Hurov et al, 2004;Motegi et al, 2011;Plant et al, 2003;Ramanujam et al, 2018;Yamanaka et al, 2003). For these experiments we made use of integrated LGL-1::GFP transgene (Waaijers et al, 2015) and an endogenously tagged PAR-1::GFP fusion.…”

Section: Par-6 and Pkc-3 Mediate Apical Lgl-1 Exclusion And Promote Jmentioning

confidence: 99%

Epidermal PAR-6 and PKC-3 are essential for postembryonic development ofCaenorhabditis elegansand control non-centrosomal microtubule organization

Castiglioni

Pires

Bertolini

et al. 2020

Preprint

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The cortical polarity regulators PAR-6, PKC-3 and PAR-3 are essential for the polarization of a broad variety of cell types in multicellular animals, from the first asymmetric division of the C. elegans zygote to apical–basal polarization of epithelial cells. In C. elegans, the roles of the PAR proteins in embryonic development have been extensively studied, yet little is known about their functions during larval development. Using auxin-inducible protein depletion, we here show that PAR-6 and PKC-3, but not PAR-3, are essential for postembryonic development. We also demonstrate that PAR-6 and PKC-3 are required in the epidermal epithelium to support animal growth and molting, and the proper timing and pattern of seam cell divisions. Finally, we uncovered a novel role for PAR-6 in controlling the organization of non-centrosomal microtubule arrays in the epidermis. PAR-6 was required for the localization of the microtubule organizer NOCA-1/Ninein, and microtubule defects in a noca-1 mutant are highly similar to those caused by epidermal PAR-6 depletion. As NOCA-1 physically interacts with PAR-6, we propose that PAR-6 promotes non-centrosomal microtubule organization through localization of NOCA-1/Ninein.SummaryUsing inducible protein degradation, we show that PAR-6 and PKC-3/aPKC are essential for postembryonic development of C. elegans and control the organization of non-centrosomal microtubule bundles in the epidermis, likely through recruitment of NOCA-1/Ninein.

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“…Regulated binding of plasma membrane lipids has emerged as a common theme. The polarity-related proteins Par1, Lgl, Miranda, Numb, PAR-2 and the anterior protein Par3 share a common ability to bind anionic phospholipids, most likely the plasma membrane-enriched PIP2, via dedicated domains [31][32][33][34][35][36]. A shared characteristic of numerous polarity-related proteins, these domains are often the direct targets of regulatory kinases, allowing membrane association to be regulated in time and space.…”

Section: Local Retentionmentioning

confidence: 99%

“…Instead, molecules typically engage in multivalent association with the membrane through the formation of homo-or hetero-dimeric complexes (Figure 2A). PAR-2 and Par3 form homo-oligomers [30,38], while PAR-1 and the related MARK kinases are thought to require coincident binding to plasma membrane lipids along with additional accessory factors, such as the C. elegans PAR-2 protein, to achieve maximal membrane enrichment [31]. In the case of Par3, it is precisely these higher-order, multivalent interactions that allow formation of stable, slow-diffusing, membrane-associated clusters that are segregated by cortical flows as discussed above and which likely play a role in numerous systems [38,39].…”

Section: Local Retentionmentioning

confidence: 99%

Switching states: dynamic remodelling of polarity complexes as a toolkit for cell polarization

Péglion

Goehring

2019

Current Opinion in Cell Biology

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Polarity is defined by the segregation of cellular components along a defined axis. To polarize robustly, cells must be able to break symmetry and subsequently amplify these nascent asymmetries. Finally, asymmetric localization of signaling molecules must be translated into functional regulation of downstream effector pathways. Central to these behaviors are a diverse set of cell polarity networks. Within these networks, molecules exhibit varied behaviors, dynamically switching among different complexes and states, active vs inactive, bound vs unbound, immobile vs diffusive. This ability to switch dynamically between states is intimately connected to the ability of molecules to generate asymmetric patterns within cells. Focusing primarily on polarity pathways governed by the conserved PAR proteins, we discuss strategies enabled by these dynamic behaviors that are used by cells to polarize. We highlight not only how switching between states is linked to the ability of polarity proteins to localize asymmetrically, but also how cells take advantage of 'state switching' to regulate polarity in time and space.

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Establishment of the PAR-1 cortical gradient by the aPKC-PRBH circuit

Cited by 22 publications

References 55 publications

Distinct activities of Scrib module proteins organize epithelial polarity

Distinct activities of Scrib module proteins organize epithelial polarity

Epidermal PAR-6 and PKC-3 are essential for postembryonic development ofCaenorhabditis elegansand control non-centrosomal microtubule organization

Switching states: dynamic remodelling of polarity complexes as a toolkit for cell polarization

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