CKIɛ/discs overgrown Promotes Both Wnt-Fz/β-Catenin and Fz/PCP Signaling in Drosophila

SummaryThe related Wnt-Frizzled(Fz)/β-catenin and Fz/planar cell polarity (PCP) pathways are essential for the regulation of numerous developmental processes and are deregulated in many human diseases. Both pathways require members of the Dishevelled (Dsh or Dvl) family of cytoplasmic factors for signal transduction downstream of the Fz receptors. Dsh family members have been studied extensively, but their activation and regulation remains largely unknown. In particular, very little is known about how Dsh differentially signals to the two pathways. Recent work in cell culture has suggested that phosphorylation of Dsh by Casein Kinase I epsilon (CKIɛ) may act as a molecular “switch,” promoting Wnt/β-catenin while inhibiting Fz/PCP signaling [1]. Here, we demonstrate in vivo in Drosophila through a series of loss-of-function and coexpression assays that CKIɛ acts positively for signaling in both pathways, rather than as a switch. Our data suggest that the kinase activity of CKIɛ is required for peak levels of Wnt/β-catenin signaling. In contrast, CKIɛ is a mandatory signaling factor in the Fz/PCP pathway, possibly through a kinase-independent mechanism. Furthermore, we have identified the primary kinase target residue of CKIɛ on Dsh. Thus, our data suggest that CKIɛ modulates Wnt/β-catenin and Fz/PCP signaling pathways via kinase-dependent and -independent mechanisms

Meiotic spindle stability depends on MAPK-interacting and spindle-stabilizing protein (MISS), a new MAPK substrate

Vertebrate oocytes arrest in the second metaphase of meiosis (metaphase II [MII]) by an activity called cytostatic factor (CSF), with aligned chromosomes and stable spindles. Segregation of chromosomes occurs after fertilization. The Mos/…/MAPK (mitogen-activated protein kinases) pathway mediates this MII arrest. Using a two-hybrid screen, we identified a new MAPK partner from a mouse oocyte cDNA library. This protein is unstable during the first meiotic division and accumulates only in MII, where it localizes to the spindle. It is a substrate of the Mos/…/MAPK pathway. The depletion of endogenous RNA coding for this protein by three different means (antisense RNA, double-stranded [ds] RNA, or morpholino oligonucleotides) induces severe spindle defects specific to MII oocytes. Overexpressing the protein from an RNA not targeted by the morpholino rescues spindle destabilization. However, dsRNA has no effect on the first two mitotic divisions. We therefore have discovered a new MAPK substrate involved in maintaining spindle integrity during the CSF arrest of mouse oocytes, called MISS (for MAP kinase–interacting and spindle-stabilizing protein)

The Drosophila GIPC Homologue Can Modulate Myosin Based Processes and Planar Cell Polarity but Is Not Essential for Development

Epithelia often show, in addition to the ubiquitous apico-basal (A/B) axis, a polarization within the plane of the epithelium, perpendicular to the A/B axis. Such planar cell polarity (PCP) is for example evident in the regular arrangement of the stereocilia in the cochlea of the mammalian inner ear or in (almost) all Drosophila adult external structures. GIPCs (GAIP interacting protein, C terminus) were first identified in mammals and bind to the Gαi GTPase activating protein RGS-GAIP. They have been proposed to act in a G-protein coupled complex controlling vesicular trafficking. Although GIPCs have been found to bind to numerous proteins including Frizzled receptors, which participate in PCP establishment, there is little in vivo evidence for the functional role(s) of GIPCs. We show here that overexpressed Drosophila dGIPC alters PCP generation in the wing. We were however unable to find any binding between dGIPC and the Drosophila receptors Fz1 and Fz2. The effect of overexpressed dGIPC is likely due to an effect on the actin cytoskeleton via myosins, since it is almost entirely suppressed by removing a genomic copy of the Myosin VI/jaguar gene. Surprisingly, although dGIPC can interfere with PCP generation and myosin based processes, the complete loss-of-function of dGIPC gives viable adults with no PCP or other detectable defects arguing for a non-essential role of dGIPC in viability and normal Drosophila development

Su(dx) E3 ubiquitin ligase–dependent and –independent functions of Polychaetoid, the Drosophila ZO-1 homologue

Polychaetoid coordinates receptor trafficking and signaling with adherens junction organization

Notch inhibits Yorkie activity in Drosophila wing discs.

During development, tissues and organs must coordinate growth and patterning so they reach the right size and shape. During larval stages, a dramatic increase in size and cell number of Drosophila wing imaginal discs is controlled by the action of several signaling pathways. Complex cross-talk between these pathways also pattern these discs to specify different regions with different fates and growth potentials. We show that the Notch signaling pathway is both required and sufficient to inhibit the activity of Yorkie (Yki), the Salvador/Warts/Hippo (SWH) pathway terminal transcription activator, but only in the central regions of the wing disc, where the TEAD factor and Yki partner Scalloped (Sd) is expressed. We show that this cross-talk between the Notch and SWH pathways is mediated, at least in part, by the Notch target and Sd partner Vestigial (Vg). We propose that, by altering the ratios between Yki, Sd and Vg, Notch pathway activation restricts the effects of Yki mediated transcription, therefore contributing to define a zone of low proliferation in the central wing discs

Adherens Junction and E-Cadherin complexes regulation by epithelial polarity: Adherens junctions regulation by polarity

International audienceE-Cadherin-based Adherens Junctions (AJs) are a defining feature of all epithelial sheets. Through the homophilic association of E-Cadherin molecules expressed on neighboring cells, they ensure intercellular adhesion amongst epithelial cells, and regulate many key aspects of epithelial biology. While their adhesive role requires these structures to remain stable, AJs are also extremely plastic. This plasticity allows for the adaptation of the cell to its changing environment: changes in neighbors after cell division, cell death, or cell movement, and changes in cell shape during differentiation. In this review we focus on the recent advances highlighting the critical role of the apico-basal polarity machinery, and in particular of the Par3/Bazooka scaffold, in the regulation and remodeling of AJs. We propose that by regulating key phosphorylation events on the core E-Cadherin complex components, Par3 and epithelial polarity promote meta-stable protein complexes governing the correct formation, localization, and functioning of AJ

MAGIs: Junctional Scaffolds Linking Inter-Cellular Junction Architecture, Actin Cytoskeleton Dynamics, and Signaling Pathways

International audienceMAGIs (membrane-associated guanylate-kinases (MAGUK) inverted) are apical scaffolds conserved across evolution, which regulate cellular junctions. Low expression of MAGIs has been associated with tumorigenesis in a wide variety of cancers. This "tumor-suppressive" function of MAGIs has stimulated many studies to better understand the processes they control, and how their misregulation could contribute to cancer progression. In this mini review, we will describe and discuss the recent advances concerning the role of MAGIs, and propose a potential framework to explain the link between the junctional role of MAGIs and the variety of signaling pathways found altered upon MAGIs loss in cancer cells. We argue that through the diversity of MAGIs' partners at the cell junctions, their impact on actin dynamics regulation, and the cellular contexts (other scaffolds or other actin regulators such as the AMOTs, NF2, etc.), the loss of MAGIs impacts different pathways, such as the PTEN/Akt, β-catenin, Hippo/YAP, or p38 pathways, to fuel tumorigenicity

VOIES DE SIGNALISATION ACTIVEES EN AVAL DES RECEPTEURS DES WNT DE TYPE FRIZZLED. ANALYSE FONCTIONNELLE DE FRIZZLED 7 AU COURS DU DEVELOPPEMENT PRECOCE CHEZ XENOPUS LAEVIS

AU COURS DE MA THESE, JE ME SUIS INTERESSE AUX SIGNALISATIONS WNT / FRIZZLED CHEZ LE XENOPE. LORS D'UNE ETUDE EN COLLABORATION, NOUS AVONS ETUDIE L'ACTIVATION DE LA VOIE -CATENINE PAR LES RECEPTEURS FRIZZLED ET IDENTIFIE UN MOTIF CONSERVE KTXXXW, LOCALISE DANS LA REGION CYTOPLASMIQUE C-TERMINALE, REQUIS A LA FOIS POUR L'ACTIVATION DE LA VOIE ET POUR LA RELOCALISATION SOUS-MEMBRANAIRE DE DISHEVELLED. J'AI ENSUITE ANALYSE LE ROLE DE XFZ7, UN NOUVEAU FRIZZLED DE XENOPE, AU COURS DES MOUVEMENTS DE CONVERGENCE ET D'EXTENSION DU MESODERME LORS DE LA GASTRULATION. J'AI MONTRE QU'IL AGISSAIT VIA DISHEVELLED ET LA PETITE PROTEINE G CDC42. MON TRAVAIL APPORTE DES RESULTATS ORIGINAUX DANS LE DOMAINE DE RECHERCHE WNT / FRIZZLED. (1) CHAQUE FRIZZLED QUI PRESENTE UN MOTIF KTXXXW EST CAPABLE DE TRANSDUIRE UN SIGNAL -CATENINE. (2) L'ACTIVATION DE LA VOIE -CATENINE ET LE RECRUTEMENT DE DISHEVELLED PAR LES FRIZZLED SONT CERTAINEMENT DEUX EVENEMENTS LIES. (3) NOUS AVONS ETE LES PREMIERS A MONTRER L'IMPLICATION D'UN RECEPTEUR FRIZZLED (XFZ7) DANS LE CONTROLE DE LA GASTRULATION DES VERTEBRES VIA UNE VOIE DE TRANSDUCTION QUI SERAIT HOMOLOGUE DE LA VOIE DE POLARITE PLANAIRE DE LA DROSOPHILE. (4) UN MEME RECEPTEUR FRIZZLED, XFZ7, PEUT ACTIVER 2 VOIES DE TRANSDUCTION (LA VOIE -CATENINE ET UNE VOIE DE TYPE POLARITE). CE RESULTAT A ETE CONFIRME PAR LA DECOUVERTE CHEZ LA DROSOPHILE QUE DFZ1 PEUT AUSSI ACTIVER LES DEUX VOIES.PARIS-BIUSJ-Thèses (751052125) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

dGIPC is enriched in midline glial cells.

<p>In all panels, E-Cadherin is shown in magenta (A–F) and dGIPC in green (A–F) or white (A′–F′). <b>A</b>. dGIPC is enriched in discrete structures in 3^rd instar larval ganglions (yellow arrowhead). <b>B</b>. In ovarian epithelial follicular cells, dGIPC is expressed at low levels and in discrete puncta (yellow arrowhead). <b>C–D</b>. dGIPC is enriched in the midline glia in stage 16 embryos (yellow arrowheads). C: ventral view, D: lateral view. <b>E–F</b>. dGIPC is enriched in the midline glia in 3^rd instar larval brain (yellow arrowhead). E: wild-type larva, F: <i>dGIPC^ex31/Df(2R)ED1725</i> null mutant larva.</p