Trimeric G Protein-Dependent Frizzled Signaling in Drosophila

Katanaev, Vladimir L.; Ponzielli, Romina; Sémériva, Michel; Tomlinson, Andrew

doi:10.1016/j.cell.2004.11.014

Cited by 255 publications

(315 citation statements)

References 47 publications

(4 reference statements)

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“…Inhibition of G ao affected the interaction of Axin2 and GSK3 but not the interaction of Axin and GSK3, whereas inhibition of G aq had the opposite effect . As G-proteins function downstream of Frizzled (Liu et al, 2001b;Katanaev et al, 2005), this result indicates that two parallel pathways mediated by different G proteins differentially regulate Axin and Axin2. However, it is still not clear why GSK3 dissociates from Axin in response to Wnt signaling in 3T3-L1 cells, whereas it remains bound in L929 cells.…”

Section: B-cateninmentioning

confidence: 94%

β-Catenin destruction complex: insights and questions from a structural perspective

2006

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At the heart of the canonical Wnt signaling pathway is the b-catenin destruction complex, which functions in the absence of Wnt signaling to keep the cytosolic and nuclear levels of b-catenin very low by promoting the phosphorylation and ubiquitination of b-catenin. Structural studies, combined with other experimental approaches, have begun to provide important insights into the mechanism of the destruction complex. We suggest a working model for the destruction complex based on the existing structural and experimental data, and focus on the questions that this model and other studies have raised about the function of the complex in both the normal and Wnt-inhibited states.

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Section: B-cateninmentioning

confidence: 94%

β-Catenin destruction complex: insights and questions from a structural perspective

2006

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“…WTX, which is vertebrate specific, thus has dichotomic roles in Wnt signaling, analogous to those for Axin and GSK3. The FZD topology invites GPCR comparisons, and FZD coupling to trimeric G-proteins in Wnt/b-catenin signaling has received certain support from pharmacological and genetic studies (Ahumada et al 2002;Katanaev et al 2005;Liu et al 2005;Schulte and Bryja 2007), although this remains a debated issue. Although Gao and Gaq are suggested to regulate Axin-GSK3 interaction (Liu et al 2005), Gbg is shown to be in complex with LRP6, DVL, and Axin and to recruit GSK3 to phosphorylate LRP6 (Jernigan et al 2010).…”

Section: Lrp6 Phosphorylation: Roles Of Pip2 G-protein and Other Kimentioning

confidence: 99%

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

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

506

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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“…One possibility is through Fz-mediated G protein signaling. Studies in both mammalian cell culture and Drosophila (Katanaev et al 2005) suggest Gao is required for Wnt/bcat signaling. This requirement is upstream of Dvl (Katanaev et al 2005), suggesting a model in which information is passed from Fz to Gao to Dvl (Fig.…”

Section: Pip5kmentioning

confidence: 99%

Wnt Signaling from Development to Disease: Insights from Model Systems

Cadigan¹,

Peifer²

2009

Cold Spring Harbor Perspectives in Biology

274

259

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One of the early surprises in the study of cell adhesion was the discovery that b-catenin plays dual roles, serving as an essential component of cadherin-based cell -cell adherens junctions and also serving as the key regulated effector of the Wnt signaling pathway. Here, we review our current model of Wnt signaling and discuss how recent work using model organisms has advanced our understanding of the roles Wnt signaling plays in both normal development and in disease. These data help flesh out the mechanisms of signaling from the membrane to the nucleus, revealing new protein players and providing novel information about known components of the pathway.

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Trimeric G Protein-Dependent Frizzled Signaling in Drosophila

Cited by 255 publications

References 47 publications

β-Catenin destruction complex: insights and questions from a structural perspective

β-Catenin destruction complex: insights and questions from a structural perspective

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

Wnt Signaling from Development to Disease: Insights from Model Systems

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