Tumor Suppressor Lzap Suppresses Wnt/β-Catenin Signaling to Promote Zebrafish Embryonic Ventral Cell Fates via the Suppression of Inhibitory Phosphorylation of Glycogen Synthase Kinase 3

Lin, Kun-Yang; Kao, Shih-Han; Lai, Chun-Ming; Chen, Ciao-Ting; Wu, Chang‐Yi; Hsu, Hwei-Jan; Wang, Wen-Der

doi:10.1074/jbc.m115.669309

Cited by 10 publications

(18 citation statements)

References 63 publications

(84 reference statements)

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“…In HNSCCs, CDK5RAP3 was shown to suppress NF-κB by reducing the phosphorylation of RelA [ 12 ]. Lin KY et al found that CDK5RAP3 also suppressed Wnt/β-catenin signaling via the suppression of GSK-3β phosphorylation in zebrafish embryos [ 17 ]. However, how CDK5RAP3 suppresses GSK-3β phosphorylation is not well understood.…”

Section: Discussionmentioning

confidence: 99%

CDK5RAP3 suppresses Wnt/β-catenin signaling by inhibiting AKT phosphorylation in gastric cancer

Zheng

Wang

Lin

et al. 2018

J Exp Clin Cancer Res

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BackgroundCDK5RAP3 was initially isolated as a binding protein of the CDK5 activator p35. Although CDK5RAP3 has been shown to negatively regulate the Wnt/β-catenin signaling pathway in gastric cancer by repressing GSK-3β phosphorylation, its in-depth mechanism has not been determined.MethodsFollowing CDK5RAP3 overexpression or knock down, CDK5RAP3 signaling pathways were investigated in gastric cancer cells by Western Blotting. Cell growth, invasion and migration were also evaluated in gastric cancer cell lines. We analyzed CDK5RAP3, AKT, p-AKT (Ser473), GSK-3β and p-GSK-3β (Ser9) expression in gastric tumor samples and adjacent non-tumor tissues from 295 patients using immunohistochemistry and Western Blotting. The prognostic significance of CDK5RAP3 and p-AKT (Ser473) was confirmed by a Log-rank test.ResultsOur study demonstrated that the expression of p-AKT (Ser473) and p-GSK-3β (Ser9) was negatively correlated with CDK5RAP3 in stable gastric cancer cell lines. CDK5RAP3 repressed AKT phosphorylation, which promoted GSK-3β phosphorylation, thereby suppressing β-catenin protein expression and, consequently, gastric cancer. The protein level of CDK5RAP3 was markedly decreased in most gastric tumor tissues compared with adjacent non-tumor tissues, and the levels of p-AKT (Ser473) and p-GSK-3β (Ser9) were also negatively correlated with those of CDK5RAP3. The prognostic value of CDK5RAP3 for overall survival was found to be dependent on AKT phosphorylation.ConclusionOur results demonstrated that CDK5RAP3 negatively regulates the Wnt/β-catenin signaling pathway by repressing AKT phosphorylation, which leads to better survival of patients with gastric cancer.

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Section: Discussionmentioning

confidence: 99%

CDK5RAP3 suppresses Wnt/β-catenin signaling by inhibiting AKT phosphorylation in gastric cancer

Zheng

Wang

Lin

et al. 2018

J Exp Clin Cancer Res

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“…Moreover, the Twa1a morphants showed reduced expression of the dorsal markers chordin , goosecoid and otx2 , and expanded expression of the ventral markers eve1 and gata2 ( Figure 7C and 7D ) 38 . To test if these defects were caused by Wnt signaling deficiency, we examined the expression of the maternal Wnt target gene bozozok ( boz ) 39 , 40 , and found that depletion of Twa1a markedly decreased boz expression ( Figure 7E and 7F ). Importantly, all of these ventralized phenotypes were efficiently reversed by morpholino-resistant Twa1 mRNA, but not by morpholino-resistant Twa1 -Δ CRA mRNA ( Figure 7 ).…”

Section: Resultsmentioning

confidence: 99%

“…Wild-type zebrafish (strain AB) were maintained at 28.5 °C using standard protocols. Procedures for animal staging and injection were performed as described 37 , 38 , 39 , 40 . Synthetic RNAs were transcribed in vitro using pCS2-Twa1a, Twa1b or Twa1a-ΔCRA vectors with MessageMachine (Ambion).…”

Section: Methodsmentioning

confidence: 99%

“…For in situ hybridization, the sequences of probes ( boz , chordin , eve1 , gata2 , gsc and otx2 ) were amplified from zebrafish cDNAs and cloned into pCS2+ vectors 37 , 38 , 39 , 40 . All constructs were confirmed by DNA sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…The probes were labeled using the Digoxigenin labeling kit (Roche). Whole-mount in situ hybridization was carried out as described previously 37 , 38 , 39 , 40 .…”

Section: Methodsmentioning

confidence: 99%

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Twa1/Gid8 is a β-catenin nuclear retention factor in Wnt signaling and colorectal tumorigenesis

Xie

Zhang

et al. 2017

Cell Res

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Hyperactivation of Wnt/β-catenin signaling is one of the major causes of human colorectal cancer (CRC). A hallmark of Wnt signaling is the nuclear accumulation of β-catenin. Although β-catenin nuclear import and export have been widely investigated, the underlying mechanism of β-catenin's nuclear retention remains largely unknown. Here, we report that Twa1/Gid8 is a key nuclear retention factor for β-catenin during Wnt signaling and colorectal carcinogenesis. In the absence of Wnt, Twa1 exists together with β-catenin in the Axin complex and undergoes ubiquitination and degradation. Upon Wnt signaling, Twa1 translocates into the nucleus, where it binds and retains β-catenin. Depletion of Twa1 attenuates Wnt-stimulated gene expression, dorsal development of zebrafish embryos and xenograft tumor growth of CRC cells. Moreover, nuclear Twa1 is significantly upregulated in human CRC tissues, correlating with the nuclear accumulation of β-catenin and poor prognosis. Thus, our results identify Twa1 as a previously undescribed regulator of the Wnt pathway for promoting colorectal tumorigenesis by facilitating β-catenin nuclear retention.

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CDK5RAP3, a key defender of udder, modulates NLRP3 inflammasome activation by regulating autophagolysosome degradation in S. agalactiae-infected mastitis

Yan

Zhou

Wang

et al. 2023

International Journal of Biological Macromolecules

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Tumor Suppressor Lzap Suppresses Wnt/β-Catenin Signaling to Promote Zebrafish Embryonic Ventral Cell Fates via the Suppression of Inhibitory Phosphorylation of Glycogen Synthase Kinase 3

Cited by 10 publications

References 63 publications

CDK5RAP3 suppresses Wnt/β-catenin signaling by inhibiting AKT phosphorylation in gastric cancer

CDK5RAP3 suppresses Wnt/β-catenin signaling by inhibiting AKT phosphorylation in gastric cancer

Twa1/Gid8 is a β-catenin nuclear retention factor in Wnt signaling and colorectal tumorigenesis

CDK5RAP3, a key defender of udder, modulates NLRP3 inflammasome activation by regulating autophagolysosome degradation in S. agalactiae-infected mastitis

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