Inhibition of Wnt Signaling Pathway by a Novel Axin-binding Protein

Kadoya, Takayuki; Kishida, Shosei; Fukui, Akimasa; Hinoi, Takao; Michiue, Tatsuo; Asashima, Makoto; Kikuchi, Akira

doi:10.1074/jbc.m005984200

Cited by 56 publications

(80 citation statements)

References 51 publications

(77 reference statements)

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“…Functional interaction between WWOX and Wnt pathway N Bouteille et al WWOX does not inhibit the interaction of Dvl-2 with the b-catenin-degradation complex In the b-catenin-degradation complex, Dvl-2 binds directly to Axin. This interaction seems to be crucial for Dvl-2 to inhibit glycogen synthase kinase 3b-dependent degradation of b-catenin (Kishida et al, 1999Smalley et al, 1999;Kadoya et al, 2000;Hino et al, 2001). WWOX would therefore inhibit the function of Dvl-2 in the Wnt/b-catenin pathway by disrupting Dvl-2-Axin association.…”

Section: Binding Domainsmentioning

confidence: 99%

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

et al. 2009

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The WWOX gene encodes a candidate tumor suppressor protein (WWOX) implicated in a variety of human diseases such as cancer. To better understand the molecular mechanisms of WWOX action, we investigated novel partners of this protein. Using the two-hybrid system and a coimmunoprecipitation assay, we observed a physical association between WWOX and the Dishevelled protein (Dvl) family signaling elements involved in the Wnt/b-catenin pathway. We found that enforced WWOX expression inhibited, and inhibition of endogenous WWOX expression stimulated the transcriptional activity of the Wnt/b-catenin pathway. Inhibition of endogenous WWOX expression also enhanced the effect of Wnt-3a on b-catenin stability. Moreover, we observed the sequestration of Dvl-2 wild type and Dvl-2NESm, a mutated form of Dvl-2 predominantly localized in the nucleus, in the cytoplasm compartment by WWOX. Our results indicate that WWOX is a novel inhibitor of the Wnt/b-catenin pathway. WWOX would act, at least in part, by preventing the nuclear import of the Dvl proteins.

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Section: Binding Domainsmentioning

confidence: 99%

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

et al. 2009

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“…These results suggest that the region containing amino acid residues 438 -529 is important for the complex formation with CKI⑀. Because this region is different from the Dvl binding site (rAxin-(508 -620)) (22), CKI⑀ and Dvl-1 could form a complex with Axin through its different regions. To examine the direct interaction of Axin with CKI⑀, GST-rAxin-(298 -832) and MBP-CKI⑀ were purified from E. coli.…”

Section: Complex Formation Of Cki⑀ With Dvl or Axin At Endogenousmentioning

confidence: 99%

“…Although whether Dvl binds directly to Frizzled, the receptor for Wnt, or whether intermediary proteins are involved in the signal transmission between Frizzled and Dvl is not known at present, Dvl appears to bind to the Axin complex (19 -21) and to inhibit GSK-3␤-dependent phosphorylation of ␤-catenin, APC, and Axin (18,20,22). Once the phosphorylation of ␤-catenin is reduced, it dissociates from the Axin complex, and ␤-catenin is no longer degraded, resulting in its accumulation in the cytoplasm.…”

mentioning

confidence: 99%

Synergistic Activation of the Wnt Signaling Pathway by Dvl and Casein Kinase Iε

Kishida¹,

Hino²,

Michiue³

et al. 2001

Journal of Biological Chemistry

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110

108

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“…Outside of their conserved catalytic domain, these proteases possess nonconserved N-terminal extensions of varying lengths and relatively short non-conserved C-terminal sequences. SENP2 was discovered both through its homology to other SUMO proteases (7) and its interactions with murine Axin, a regulator of the Wnt signaling pathway (12). When overexpressed in tissue culture cells or under in vitro conditions, the murine SENP2 homologue (Smt3IP2) cleaves conjugates of SUMO-1, SUMO-2, and SUMO-3 (11).…”

Section: Sumo-1mentioning

confidence: 99%

Association of the Human SUMO-1 Protease SENP2 with the Nuclear Pore

Hang

Dasso

2002

Journal of Biological Chemistry

221

184

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SUMO-1 is a small ubiquitin-like protein that can be covalently conjugated to other proteins. A family of proteases catalyzes deconjugation of SUMO-1-containing species. Members of this family also process newly synthesized SUMO-1 into its conjugatable form. To understand these enzymes better, we have examined the localization and behavior of the human SUMO-1 protease SENP2. Here we have shown that SENP2 associates with the nuclear face of nuclear pores and that this association requires protein sequences near the N terminus of SENP2. We have also shown that SENP2 binds to Nup153, a nucleoporin that is localized to the nucleoplasmic face of the pore. Nup153 binding requires the same domain of SENP2 that mediates its targeting in vivo. Removal of the Nup153-interacting region of SENP2 results in a significant change in the spectrum of SUMO-1 conjugates within the cell. Our results suggest that association with the pore plays an important negative role in the regulation of SENP2, perhaps by restricting its activity to a subset of the conjugated proteins within the nucleus. SUMO-11 is a ubiquitin-like protein that can be covalently conjugated to other proteins through an isopeptide linkage in a manner similar to ubiquitin (1). The SUMO-1 conjugation pathway utilizes proteins that both show sequence similarity to analogous enzymes in the ubiquitin pathway and utilize similar biochemical mechanisms (1). A large and growing number of SUMO-1 conjugation substrates have been reported in vertebrates (1). Notably, the profile of SUMO-1-conjugated proteins changes substantially in response to altered cellular conditions (see Ref. 2), suggesting that there are mechanisms to control the specificity of conjugation and/or deconjugation of SUMO-1 differentially between distinct substrates.Unlike enzymes of the SUMO-1 conjugation pathway, enzymes involved in SUMO processing and deconjugation are not closely related by sequence to their ubiquitin counterparts. Rather, known SUMO proteases share sequence homology in their catalytic domains, which is more nearly conserved to viral proteases (3). Two SUMO proteases have been described in budding yeast, Ulp1p (3) and Ulp2p/Smt4p (4, 5). Ulp1p is concentrated near the nuclear periphery (5) and interacts with nuclear pore components in two-hybrid assays (6), while Ulp2p is localized throughout the nucleus (5). ULP1 is an essential gene, and temperature-sensitive (ts) Ulp1p mutants arrest at the G2/M transition of the cell cycle. Ulp2 is not essential, but it is required for normal meiotic development, for regulation of spindle checkpoint arrest, and for chromatin condensation of rDNA during mitosis (4, 5). Interestingly, these proteins do not appear to act in a simple complementary manner, since ulp1-ts/ulp2-null double mutants grow better than ulp2 single mutants under a variety of conditions (5).In mammals, data base searches find at least seven members of the SUMO protease family (7), some of which have now been confirmed to act as SUMO proteases in vitro (8 -11). Outside of their c...

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Inhibition of Wnt Signaling Pathway by a Novel Axin-binding Protein

Cited by 56 publications

References 51 publications

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

Synergistic Activation of the Wnt Signaling Pathway by Dvl and Casein Kinase Iε

Association of the Human SUMO-1 Protease SENP2 with the Nuclear Pore

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