The Wnt Signaling Antagonist Dapper1 Accelerates Dishevelled2 Degradation via Promoting Its Ubiquitination and Aggregate-induced Autophagy

Ma, Benyu; Liu, Bofeng; Cao, Weipeng; Gao, Chan; Qi, Zhengjian; Ning, Yuanheng; Chen, Ye-Guang

doi:10.1074/jbc.m115.654590

Cited by 39 publications

(39 citation statements)

References 42 publications

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“…Dvl proteins can undergo degradation via either the proteasome or the autophagy-lysosome pathway (5, 8 -10, 31). We have shown that Dvl recruitment to autophagosomes could be facilitated by Dapper1 (12,19). In this study, we identified RACK1 as a novel regulator to control Dvl stability by enhancing the interaction between Dvl and LC3 and thus enhancing their autophagic degradation.…”

Section: Discussionmentioning

confidence: 89%

“…We observed that RACK1 could interact with both Dvl and LC3 and promote Dvl recruitment to the autophagosome and its degradation in the lysosome. Interestingly, RACK1 can interact with pVHL (32) and Dapper1 (data not shown), both of which facilitate Dvl recruitment to autophagosome via ubiquitination or protein-protein interaction (10,12). It remains unclear at this moment whether RACK1 has any functional interactions with pVHL or Dapper in promoting Dvl degradation.…”

Section: Discussionmentioning

confidence: 99%

“…We have also demonstrated that Dvl proteins can be degraded via autophagy after ubiquitinated by von HippelLindau tumor suppressor (pVHL) (10). Dapper1, a Dvl-binding protein, acts as a scaffold protein to enhance the interaction between pVHL and Dvl and facilitates autophagic degradation of Dvl proteins (11,12).…”

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confidence: 99%

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Receptor for Activated C Kinase 1 (RACK1) Promotes Dishevelled Protein Degradation via Autophagy and Antagonizes Wnt Signaling

Cheng

Xue

Cao

et al. 2016

Journal of Biological Chemistry

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Wnt signaling plays a critical role in embryonic development, tissue homeostasis, and cancer development. Dishevelled (Dvl) is an essential and central component in Wnt signaling, and its stability and activity is tightly regulated. It has been shown that Dvl can be degraded via both the proteasome and autophagylysosome pathways. Here we report that receptor for activated C kinase 1 (RACK1) negatively regulates Dishevelled stability and Wnt signaling. RACK1 interacts with Dvl proteins and promotes their lysosomal degradation, and this effect is enhanced by autophagy induction. RACK1 also interacts with LC3 and enhances the association of LC3 with Dvl2, thereby leading to degradation of Dvl proteins through autophagy. These findings reveal a novel regulatory function of RACK1 in Wnt signaling by modulating Dvl stability.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Receptor for Activated C Kinase 1 (RACK1) Promotes Dishevelled Protein Degradation via Autophagy and Antagonizes Wnt Signaling

Cheng

Xue

Cao

et al. 2016

Journal of Biological Chemistry

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“…DACT1 is a member of the Dapper family, which includes three genes: DACT1, DACT2 and DACT3 (11). As a tumor suppressor, DACT1 is downregulated in multiple tumor types, such as liver, colon and breast cancer (12).…”

Section: Introductionmentioning

confidence: 99%

Expression of DACT1 in children with asthma and its regulation mechanism

et al. 2018

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Abstract. The aim of the present study was to detect DACT1 expression levels in the lungs of children with asthma, and to investigate its role and molecular mechanisms in regulating the expression of inflammatory factors in RAW264.7 cells. DACT1, DACT2 and DACT3 expression was analyzed in biopsy specimens from 10 cases of newly diagnosed children with asthma and 10 healthy controls by reverse transcription-quantitative polymerase chain reaction, and their expression was confirmed in RAW264.7 cells. DACT1 expression was silenced by small interfering RNA or enhanced by transfection of pcDNA-3.1-DACT1 in RAW264.7 cells, and expression of β-catenin and inflammatory factors, interleukin (IL) 5, IL6 and IL13, was analyzed. Nuclear translocation of β-catenin was detected by western blot analysis, and the effect of DACT1 on β-catenin was investigated with rescue experiments. Regulation of the Wnt signaling pathway by DACT1 and β-catenin was analyzed in RAW264.7 cells after recombinant Wnt5A stimulation. DACT1, DACT2 and DACT3 were significantly upregulated in specimens from children with asthma compared with controls (P<0.05) and the expression of DACT1 was significantly more increased compared with DACT2 and DACT3 (P<0.05). Inhibition of DACT1 expression significantly suppressed IL5, IL6 and IL13 mRNA expression levels compared with the control (P<0.05), while upregulated DACT1 expression significantly increased IL5, IL6 and IL13 mRNA expression (P<0.05). DACT1 inhibited the expression and nuclear translocation of β-catenin, while overexpression of β-catenin significantly inhibited the biological function of DACT1 (P<0.05). Overexpression of β-catenin also significantly suppressed the upregulation of IL5, IL6 and IL13 mRNA induced by pcDNA3.1-DACT1 transfection (P<0.05). Following the addition of Wnt5A, overexpression of DACT1 inhibited the expression and nuclear translocation of β-catenin, and upregulated IL5, IL6 and IL13 mRNA expression. In conclusion, DACT1 was indicated to be upregulated in lung tissues from children with asthma, which could induce higher pro-inflammatory factor expression. DACT1 may act via inhibiting the expression and nuclear translocation of β-catenin, a factor in the Wnt signaling pathway. The present results suggested that DACT1 may be a potential target for the treatment of asthma.

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“…NEDDL4 is itself regulated by phosphorylation in response to Wnt5α signaling and mediates K6, K27 and K29-linked polyubiquitination of DVL2 (10). Metabolic stress also promotes DVL2 ubiquitination by VHL that results in its aggregation and autophagic clearance (11). By contrast, the poly-ubiquitination of DVL1-3 by KLHL12 does not require a specific cell stimulus and appears to be the result of a direct and constitutive protein-protein interaction (12,13).…”

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confidence: 99%

Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12

Chen

Wasney

Picaud

et al. 2020

Preprint

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The Wnt Signaling Antagonist Dapper1 Accelerates Dishevelled2 Degradation via Promoting Its Ubiquitination and Aggregate-induced Autophagy

Cited by 39 publications

References 42 publications

Receptor for Activated C Kinase 1 (RACK1) Promotes Dishevelled Protein Degradation via Autophagy and Antagonizes Wnt Signaling

Receptor for Activated C Kinase 1 (RACK1) Promotes Dishevelled Protein Degradation via Autophagy and Antagonizes Wnt Signaling

Expression of DACT1 in children with asthma and its regulation mechanism

Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12

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