The KLHL12–Cullin-3 ubiquitin ligase negatively regulates the Wnt–β-catenin pathway by targeting Dishevelled for degradation

Angers, Stéphane; Thorpe, Chris J.; Biechele, Travis L.; Goldenberg, Seth J.; Zheng, Ning; MacCoss, Michael J.; Moon, Randall T.

doi:10.1038/ncb1381

Cited by 344 publications

(376 citation statements)

References 48 publications

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“…Printor is a novel member of the BTB-BACK-Kelch (BBK) protein family (51,56,57) and contains an N-terminal BTB homology region, a BACK domain, and six kelch repeats. Several BBK proteins have been implicated in neuronal development (58 -60) and protein ubiquitination (50,57,(61)(62)(63), and mutations in at least one BBK protein, gigaxonin, lead to neuronal dysfunction (64). A major difference between printor and other BBK proteins is that the printor BTB homology region contains a 48-amino acid P/Q-rich intervening sequence, making it difficult to predict whether this region of printor represents a functional BTB domain.…”

Section: Discussionmentioning

confidence: 99%

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Giles

Chin

2009

Journal of Biological Chemistry

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Early onset generalized dystonia (DYT1) is an autosomal dominant neurological disorder caused by deletion of a single glutamate residue (torsinA ⌬E) in the C-terminal region of the AAA ؉ (ATPases associated with a variety of cellular activities) protein torsinA. The pathogenic mechanism by which torsinA ⌬E mutation leads to dystonia remains unknown. Here we report the identification and characterization of a 628-amino acid novel protein, printor, that interacts with torsinA. Printor co-distributes with torsinA in multiple brain regions and colocalizes with torsinA in the endoplasmic reticulum. Interestingly, printor selectively binds to the ATP-free form but not to the ATP-bound form of torsinA, supporting a role for printor as a cofactor rather than a substrate of torsinA. The interaction of printor with torsinA is completely abolished by the dystoniaassociated torsinA ⌬E mutation. Our findings suggest that printor is a new component of the DYT1 pathogenic pathway and provide a potential molecular target for therapeutic intervention in dystonia.Early onset generalized torsion dystonia (DYT1) is the most common and severe form of hereditary dystonia, a movement disorder characterized by involuntary movements and sustained muscle spasms (1). This autosomal dominant disease has childhood onset and its dystonic symptoms are thought to result from neuronal dysfunction rather than neurodegeneration (2, 3). Most DYT1 cases are caused by deletion of a single glutamate residue at positions 302 or 303 (torsinA ⌬E) of the 332-amino acid protein torsinA (4). In addition, a different torsinA mutation that deletes amino acids Phe 323 -Tyr 328(torsinA ⌬323-328) was identified in a single family with dystonia (5), although the pathogenic significance of this torsinA mutation is unclear because these patients contain a concomitant mutation in another dystonia-related protein, ⑀-sarcoglycan (6). Recently, genetic association studies have implicated polymorphisms in the torsinA gene as a genetic risk factor in the development of adult-onset idiopathic dystonia (7,8).TorsinA contains an N-terminal endoplasmic reticulum (ER) 3 signal sequence and a 20-amino acid hydrophobic region followed by a conserved AAA ϩ (ATPases associated with a variety of cellular activities) domain (9, 10). Because members of the AAA ϩ family are known to facilitate conformational changes in target proteins (11,12), it has been proposed that torsinA may function as a molecular chaperone (13,14). TorsinA is widely expressed in brain and multiple other tissues (15) and is primarily associated with the ER and nuclear envelope (NE) compartments in cells (16 -20). TorsinA is believed to mainly reside in the lumen of the ER and NE (17-19) and has been shown to bind lamina-associated polypeptide 1 (LAP1) (21), lumenal domain-like LAP1 (LULL1) (21), and nesprins (22). In addition, recent evidence indicates that a significant pool of torsinA exhibits a topology in which the AAA ϩ domain faces the cytoplasm (20). In support of this topology, torsinA is found in the...

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Section: Discussionmentioning

confidence: 99%

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Giles

Chin

2009

Journal of Biological Chemistry

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“…Cells were harvested for immunoblotting or immunocytochemistry 24 h after transfection. The following plasmids have been described previously: Dvl2-Myc (42), ca-␤-catenin (43), FLAG-Dvl3 deletion constructs (32), Xenopus (x) Dsh and xPAR1 constructs (25), xCK2 constructs (44), xCK1⑀ constructs (45), GST-DSH (36), and FLAG-Dvl1 (46). Treatment with the D4476, IC261, TBBt, or TBCA (Calbiochem) dissolved in DMSO was done in 24-well plates in the presence of 1 l per well FuGENE 6 reagent to increase cell penetration.…”

Section: Methodsmentioning

confidence: 99%

“…mutants of Dvl3 (32) and analyzed the function of individual domains for Dvl3 behavior, which was modified by CK1 or CK2/PAR1. The parameters examined after CK1⑀ and in some cases after CK2 overexpression included (i) the ability to bind CK1⑀ (endogenous and overexpressed), endogenous CK2␣, and endogenous Axin1, (ii) the ability to promote TCF/LEF-dependent transcription (see Fig.…”

Section: Cmentioning

confidence: 99%

Sequential Activation and Inactivation of Dishevelled in the Wnt/β-Catenin Pathway by Casein Kinases

Bernatík

Ganji

Dijksterhuis

et al. 2011

Journal of Biological Chemistry

101

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“…Synergistic phosphorylation of Dvl2 and Dvl3 in the presence of FZD10 interested us in Dvl2/Dvl3 heterooligomerization (Rothba¨cher et al, 2000;Angers et al, 2006). To investigate this possibility, we constructed the myc-tagged-Dvl2 vector (Dvl2-myc) and transfected into FZD10-stably expressing cells (FZD10-2) or Mock cells (Mock2).…”

Section: Regulation Of Dvl2 and Dvl3 By Fzd10mentioning

confidence: 99%

Activation of the non-canonical Dvl–Rac1–JNK pathway by Frizzled homologue 10 in human synovial sarcoma

et al. 2009

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We previously reported that Frizzled homologue 10 (FZD10), a member of the Wnt signal receptor family, was highly and specifically upregulated in synovial sarcoma and played critical roles in its cell survival and growth. We here report a possible molecular mechanism of the FZD10 signaling in synovial sarcoma cells. We found a significant enhancement of phosphorylation of the Dishevelled (Dvl)2/Dvl3 complex as well as activation of the Rac1-JNK cascade in synovial sarcoma cells in which FZD10 was overexpressed. Activation of the FZD10-Dvls-Rac1 pathway induced lamellipodia formation and enhanced anchorage-independent cell growth cells. FZD10 overexpression also caused the destruction of the actin cytoskeleton structure, probably through the downregulation of the RhoA activity. Our results have strongly implied that FZD10 transactivation causes the activation of the non-canonical Dvl-Rac1-JNK pathway and plays critical roles in the development/progression of synovial sarcomas.

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The KLHL12–Cullin-3 ubiquitin ligase negatively regulates the Wnt–β-catenin pathway by targeting Dishevelled for degradation

Cited by 344 publications

References 48 publications

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Sequential Activation and Inactivation of Dishevelled in the Wnt/β-Catenin Pathway by Casein Kinases

Activation of the non-canonical Dvl–Rac1–JNK pathway by Frizzled homologue 10 in human synovial sarcoma

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