The Apical Determinants aPKC and dPatj Regulate Frizzled-Dependent Planar Cell Polarity in the Drosophila Eye

Djiane, Alexandre; Yogev, Shaul; Mlodzik, Marek

doi:10.1016/j.cell.2005.03.014

Cited by 167 publications

(167 citation statements)

References 44 publications

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“…1A). The cytoplasmic C-terminal tail of Fz contains a conserved motif (KTxxxW) that is essential for signaling and for membrane relocalization of Dvl (9,14,15). Microinjection of peptides comprising this motif interferes with Wnt/β-catenin signaling in Xenopus embryos, further supporting the functional importance of the Fz C-terminal tail.…”

mentioning

confidence: 90%

Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

Tauriello

Jordens

Kirchner

et al. 2012

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

197

218

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Wnt binding to members of the seven-span transmembrane Frizzled (Fz) receptor family controls essential cell fate decisions and tissue polarity during development and in adulthood. The Fzmediated membrane recruitment of the cytoplasmic effector Dishevelled (Dvl) is a critical step in Wnt/β-catenin signaling initiation, but how Fz and Dvl act together to drive downstream signaling events remains largely undefined. Here, we use an Fz peptide-based microarray to uncover a mechanistically important role of the bipartite Dvl DEP domain and C terminal region (DEP-C) in binding a three-segmented discontinuous motif in Fz. We show that cooperative use of two conserved motifs in the third intracellular loop and the classic C-terminal motif of Fz is required for DEP-C binding and Wnt-induced β-catenin activation in cultured cells and Xenopus embryos. Within the complex, the Dvl DEP domain mainly binds the Fz C-terminal tail, whereas a short region at the Dvl C-terminal end is required to bind the Fz third loop and stabilize the Fz-Dvl interaction. We conclude that Dvl DEP-C binding to Fz is a key event in Wnt-mediated signaling relay to β-catenin. The discontinuous nature of the Fz-Dvl interface may allow for precise regulation of the interaction in the control of Wnt-dependent cellular responses.peptide microarray | protein-protein interaction | Wingless signaling

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mentioning

confidence: 90%

Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

Tauriello

Jordens

Kirchner

et al. 2012

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

197

218

View full text Add to dashboard Cite

show abstract

“…1A), which is commonly involved in PDZ binding (Hering and Sheng 2002) and may serve as an accessory site to augment FZD clustering by perhaps PDZ proteins. Phosphorylation of the FZD carboxyl region has been observed and is associated with down-regulation of FZD/PCP signaling, such as Fz/Dfz1 phosphorylation by aPKC around the DVL-interacting SxKTxxSW motif in Drosophila (Djiane et al 2005), and Dvl-dependent FZD3 phosphorylation, which inhibits FZD3 endocytosis and signaling, in axon guidance (Shafer et al 2011) and possibly in neural crest induction (Yanfeng et al 2006). However, it is unknown whether phosphorylation regulates FZD function in b-catenin signaling.…”

Section: Fzd and Dvl Interactionmentioning

confidence: 99%

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

533

411

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Frizzled and LRP5/6 are Wnt receptors that upon activation lead to stabilization of cytoplasmic b-catenin. In this study, we review the current knowledge of these two families of receptors, including their structures and interactions with Wnt proteins, and signaling mechanisms from receptor activation to the engagement of intracellular partners Dishevelled and Axin, and finally to the inhibition of b-catenin phosphorylation and ensuing b-catenin stabilization.T he Wnt/b-catenin pathway, or canonical Wnt pathway as it is often referred to, is an ancient and conserved signaling cascade involving b-catenin acting as a transcriptional coactivator (Logan and Nusse 2004). The pathway is best understood when considered in a two-state model of OFF (without Wnt) and ON (with Wnt). In the OFF state, cytoplasmic b-catenin is constitutively targeted for degradation by two multidomain scaffolding proteins, Axin and Adenomatous polyposis coli (APC), which facilitate the amino-terminal phosphorylation of b-catenin via the kinases GSK3 and CKIa. Phosphorylated b-catenin is recognized by the E3 ubiquitin ligase b-Trcp and is thus ubiquitinated and degraded by the proteasome, thereby maintaining low levels of free b-catenin in the cytoplasm and nucleus (MacDonald et al. 2009). In the ON state, a Wnt ligand binds to the seven-pass transmembrane receptor Frizzled (FZD) and the single-pass low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) ). The Wnt-FZD -LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of b-catenin phosphorylation and thus ensuing b-catenin stabilization. The rise of cytoplasmic and nuclear levels of b-catenin levels promotes b-catenin partnering with the TCF/ LEF transcription factors for activation of Wntresponsive gene expression.Wnt/b-catenin signaling controls cell proliferation and differentiation and is a key regulatory mechanism for stem cells. As such, mutations in the Wnt pathway cause many diseases including cancer (Clevers 2006). All of the above "core" Wnt/b-catenin signaling components are present in vertebrates and the well-studied fruit fly Drosophila and are also encoded in sequenced genomes of radial symmetric Cnidarians Hydra magnipapillata and Nematostella vectensis (Guder et al. 2006) and of the primitive metazoan sponge Amphimedon queenslandica

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“…Planar polarity and apical-basal polarity are probably concomitant processes, sharing molecules and molecular cascades. A recent paper showed the existence of an interaction between Drosophila PALS-1 associated tight junction protein, a protein from the apical marginal region junction, and fz1 in Drosophila eye, suggesting that molecules necessary for apical-basal polarity and planar polarity can interact (Djiane et al, 2005). Another recent paper analyzed the interactions of trilobite (tri)/stbm (a zebrafish allele of Vangl2) and scrb1 (Wada et al, 2005).…”

Section: Interactions Between Vangl2 and Scrb1 Are Required For Asymmmentioning

confidence: 99%

Asymmetric Localization of Vangl2 and Fz3 Indicate Novel Mechanisms for Planar Cell Polarity in Mammals

Montcouquiol¹,

Sans²,

Huss³

et al. 2006

J. Neurosci.

287

291

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The Apical Determinants aPKC and dPatj Regulate Frizzled-Dependent Planar Cell Polarity in the Drosophila Eye

Cited by 167 publications

References 44 publications

Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

Asymmetric Localization of Vangl2 and Fz3 Indicate Novel Mechanisms for Planar Cell Polarity in Mammals

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