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

Tauriello, Daniele V.F.; Jordens, Ingrid; Kirchner, Katharina; Slootstra, Jerry W.; Kruitwagen, Tom; Bouwman, Britta A. M.; Noutsou, Maria; Rüdiger, Stefan; Schwamborn, Klaus; Schambony, Alexandra; Maurice, Madelon M.

doi:10.1073/pnas.1114802109

Cited by 183 publications

(237 citation statements)

References 49 publications

(72 reference statements)

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“…The importance of these residues for signaling has been shown by fly Fz/Dfz1 mutants, patient mutations in FZD4, and site-directed mutagenesis studies (Robitaille et al 2002;Cong et al 2004b;Zeng et al 2008;Nikopoulos et al 2010). Some of these findings can potentially be explained by DVL interaction with FZD ICL3 (Tauriello et al 2012). Whether ICL1 and ICL2 residues are also involved in interaction with DVL, or G-proteins (see below), or unidentified proteins remains to be investigated.…”

Section: Fzd and Dvl Interactionmentioning

confidence: 99%

“…1B) and the KTxxxW region (so-called motif III) (Fig. 1B), thereby facilitating DVL association with a discontinuous cytoplasmic surface of FZD (Tauriello et al 2012). Thus, PDZ and DEP domains have roles in recruiting DVL to FZD at the plasma membrane (Fig.…”

Section: The Wnt -Fzd -Lrp5/6 Complexmentioning

confidence: 99%

“…The simplest model states that DIX and PDZ domains, but not DEP, are required for Wnt/b-catenin signaling, as seen in some overexpression studies. However, evidence exists that the DEP domain influences b-catenin signaling (Wong et al 2000;Simons et al 2009;Tauriello et al 2012). DVL associates with kinases such as CK11 and CK2, and becomes hyperphosphorylated upon Wnt signaling (Willert et al 1997;Peters et al 1999;Kishida et al 2001;Cong et al 2004a;Klein et al 2006).…”

Section: The Wnt -Fzd -Lrp5/6 Complexmentioning

confidence: 99%

“…1B) (Tauriello et al 2012). Thus, multiple DVL domains/regions appear to engage a discontinuous cytoplasmic surface of FZD, and FZD -DVL association, which derives from a sum of multiple relatively weak interactions, may be further stabilized by the DEP-phospholipids (in the plasma membrane) interaction (Fig.…”

Section: Fzd and Dvl Interactionmentioning

confidence: 99%

“…1B). Given the importance of the KTxxxWregion for DVL (PDZ and/ or DEP) binding (Punchihewa et al 2009;Tauriello et al 2012), one potential mechanism for FZD activation would be a Wnt-induced movement of TM7 to expose the key FZD -DVL interaction site, if we assume that Wnt regulates FZD -DVL interaction. It should be noted that FZD -DVL interaction has thus far been studied either in vitro or under overexpression conditions in vivo, and it remains unknown whether this interaction is under Wnt regulation.…”

Section: Fzd and Dvl Interactionmentioning

confidence: 99%

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

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

495

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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Section: Fzd and Dvl Interactionmentioning

confidence: 99%

Section: The Wnt -Fzd -Lrp5/6 Complexmentioning

confidence: 99%

Section: The Wnt -Fzd -Lrp5/6 Complexmentioning

confidence: 99%

Section: Fzd and Dvl Interactionmentioning

confidence: 99%

Section: Fzd and Dvl Interactionmentioning

confidence: 99%

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

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

495

411

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Pellino‐2 in nonimmune cells: novel interaction partners and intracellular localization

et al. 2021

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Pellino‐2 is an E3 ubiquitin ligase that mediates intracellular signaling in innate immune pathways. Most studies of endogenous Pellino‐2 have been performed in macrophages, but none in nonimmune cells. Using yeast two‐hybrid screening and co‐immunoprecipitation, we identified six novel interaction partners of Pellino‐2, with various localizations: insulin receptor substrate 1, NIMA‐related kinase 9, tumor necrosis factor receptor‐associated factor 7, cyclin‐F, roundabout homolog 1, and disheveled homolog 2. Pellino‐2 showed cytoplasmic localization in a wide range of nonimmune cells under physiological potassium concentrations. Treatment with the potassium ionophore nigericin resulted in nuclear localization of Pellino‐2, which was reversed by the potassium channel blocker tetraethylammonium. Live‐cell imaging revealed intracellular migration of GFP‐tagged Pellino‐2. In summary, Pellino‐2 interacts with proteins at different cellular locations, taking part in dynamic processes that change its intracellular localization influenced by potassium efflux.

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CK1ε and p120‐catenin control Ror2 function in noncanonical Wnt signaling

et al. 2018

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Canonical and noncanonical Wnt pathways share some common elements but differ in the responses they evoke. Similar to Wnt ligands acting through the canonical pathway, Wnts that activate the noncanonical signaling, such as Wnt5a, promote Disheveled (Dvl) phosphorylation and its binding to the Frizzled (Fz) Wnt receptor complex. The protein kinase CK1ε is required for Dvl/Fz association in both canonical and noncanonical signaling. Here we show that differently to its binding to canonical Wnt receptor complex, CK1ε does not require p120‐catenin for the association with the Wnt5a co‐receptor Ror2. Wnt5a promotes the formation of the Ror2–Fz complex and enables the activation of Ror2‐bound CK1ε by Fz‐associated protein phosphatase 2A. Moreover, CK1ε also regulates Ror2 protein levels; CK1ε association stabilizes Ror2, which undergoes lysosomal‐dependent degradation in the absence of this kinase. Although p120‐catenin is not required for CK1ε association with Ror2, it also participates in this signaling pathway as p120‐catenin binds and maintains Ror2 at the plasma membrane; in p120‐depleted cells, Ror2 is rapidly internalized through a clathrin‐dependent mechanism. Accordingly, downregulation of p120‐catenin or CK1ε affects late responses to Wnt5a that are also sensitive to Ror2, such as SIAH2 transcription, cell invasion, or cortical actin polarization. Our results explain how CK1ε is activated by noncanonical Wnt and identify p120‐catenin and CK1ε as two critical factors controlling Ror2 function.

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

Cited by 183 publications

References 49 publications

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

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

Pellino‐2 in nonimmune cells: novel interaction partners and intracellular localization

CK1ε and p120‐catenin control Ror2 function in noncanonical Wnt signaling

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