• BMB Reports
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• v.43 no.9
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• pp.609-613
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• 2010

The Dvl and Axin proteins, which are involved in the Wnt signaling pathway, each contain a conserved DIX domain in their sequences. The DIX domain mediates interaction between Dvl and Axin, which together play an important role in signal transduction. However, the extremely low production of DIX domain fragments in E. coli has prevented more widespread functional and structural studies. In this study, we demonstrate that the DIX domains of Dvl and Axin are expressed noticeably in a multi-cistronic system but not in a mono-cistronic system. Formation of the $DIX_{Dvl1}-DIX_{Axin1}$ complex was investigated by affinity chromatography, SEC and crystallization studies. Unstable DIX domains were stabilized by complexing with counterpart DIX domains. The results of the preliminary crystallization and diffraction of the $DIX_{Dvl1}-DIX_{Axin1}$ complex may prove useful for further crystallographic studies.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.6
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• pp.2385-2390
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• 2015

Background: Invasive ductal (IDC) and lobular (ILC) carcinomas are the common histological types of breast carcinoma which are difficult to distinguish when poorly differentiated. Discoidin domain receptor (DDR1) and Drosophila dishevelled protein (DVL1) were recently suggested to differentiate IDC from ILC. Objectives: To assess the expression of DDR1 and DVL1 and their association with histological type, grading and hormonal status of IDC and ILC. Materials and Methods: This cross sectional study was conducted on IDC and ILC breast tumours. Tumours were immunohistochemically stained for (DDR1) and (DVL1) as well as estrogen receptor (ER), progesterone receptor (PR) and C-erbB2 receptor. Demographic data including age and ethnicity were obtained from patient records. Results: A total of 51 cases (30 IDCs and 21 ILCs) were assessed. DDR1 and DVL1 expression was not significantly associated with histological type (p=0.57 and p=0.66 respectively). There was no association between DDR1 and DVL1 expression and tumour grade (p=0.32 and p=1.00 respectively), ER (p=0.62 and 0.50 respectively), PR (p=0.38 and p=0.63 respectively) and C-erbB2 expression (p=0.19 and p=0.33 respectively) in IDC. There was no association between DDR1 and DVL1 expression and tumour grade (p=0.52 and p=0.33 respectively), ER (p=0.06 and p=0.76 respectively), PR (p=0.61 and p=0.43 respectively) and C-erbB2 expression (p=0.58 and p=0.76 respectively) in ILC. Conclusions: This study revealed that DDR1 and DVL1 are present in both IDC and ILC regardless of the tumour differentiation. More studies are needed to assess the potential of these two proteins in distinguishing IDC from ILC in breast tumours.

• BMB Reports
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• v.51 no.9
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• pp.425-426
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• 2018

As highly conserved signaling cascades of multicellular organisms, Wnt and Hippo pathways control a wide range of cellular activities, including cell adhesion, fate determination, cell cycle, motility, polarity, and metabolism. Dysregulation of those pathways are implicated in many human diseases, including cancer. Similarly to ${\beta}-catenin$ in the Wnt pathway, the YAP transcription co-activator is a major player in Hippo. Although the intracellular dynamics of YAP are well-known to largely depend on phosphorylation by LATS and AMPK kinases, the molecular effector of YAP cytosolic translocation remains unidentified. Recently, we reported that the Dishevelled (DVL), a key scaffolding protein between canonical and non-canonical Wnt pathway, is responsible for nuclear export of phosphorylated YAP. The DVL is also required for YAP intracellular trafficking induced by E-cadherin, ${\alpha}-catenin$, or metabolic stress. Note that the p53/LATS2 and LKB1/AMPK tumor suppressor axes, commonly inactivated in human cancer, govern the reciprocal inhibition between DVL and YAP. Conversely, loss of the tumor suppressor allows co-activation of YAP and Wnt independent of epithelial polarity or contact inhibition in human cancer. These observations provide novel mechanistic insight into (1) a tight molecular connection merging the Wnt and Hippo pathways, and (2) the importance of tumor suppressor contexts with respect to controlled proliferation and epithelial polarity regulated by cell adhesion.

• BMB Reports
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• v.38 no.2
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• pp.243-247
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• 2005

Dishevelled (Dvl) is a positive regulator of the canonical Wnt signaling pathway, which regulates the levels of $\beta$-catenin. The $\beta$-catenin oncoprotein depends upon the association of Dvl and Axin proteins through their DIX domains, and its accumulation directs the expression of specific developmental-related genes at the nucleus. Here, the $^1H$, $^{13}C$, and $^{15}N$ resonances of the human Dishevelled 2 DIX domain are assigned using heteronuclear nuclear magnetic resonance (NMR) spectroscopy. In addition, helical and extended elements are identified based on the NMR data. The results establish a structural context for characterizing the actin and phospholipid interactions and binding sites of this novel domain, and provide insights into its role in protein localization to stress fibers and cytoplasmic vesicles during Wnt signaling.

• Journal of Integrative Natural Science
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• v.12 no.4
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• pp.133-141
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• 2019

Mesenchymal stem cells (MSCs) are known to differentiate into multiple lineages, making neurogenic differentiation an important target in the clinical field. In the present study, we induced the neurogenic differentiation of cells using histone deacetylase (HDAC) inhibitors and studied their mechanisms for further differentiation in vitro. We treated cells with the HDAC inhibitors, MS-275 and NaB; and found that the cells had neuron-like features such as distinct bipolar or multipolar morphologies with branched processes. The mRNA expressions encoding for NEFL, MAP2, TUJ1, OLIG2, and SYT was significantly increased following HDAC inhibitors treatment compared to without HDAC inhibitors; high protein levels of MAP2 and Tuj1 were detected by immunofluorescence staining. We examined the mechanisms of differentiation and found that the Wnt signaling pathway and downstream mitogen-activate protein kinase were involved in neurogenic differentiation of MSCs. Importantly, Wnt4, Wnt5a/b, and Wnt11 protein levels were highly increased after treatment with NaB; signals were activated through the regulation of Dvl2 and Dvl3. Interestingly, NaB treatment increased the levels of JNK and upregulated JNK phosphorylation. After MS-275 treatment, Wnt protein levels were decreased and GSK-3β was phosphorylated. In this cell, HDAC inhibitors controlled the non-canonical Wnt expression by activating JNK phosphorylation and the canonical Wnt signaling by targeting GSK-3β.

• Journal of Life Science
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• v.21 no.9
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• pp.1301-1309
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• 2011

The major function of adipocytes is to store fat in the form of triglycerides. One of the signaling pathways known to affect adipogenesis, i.e. fat formation, is the WNT/${\beta}$-catenin pathway which inhibits the expression and activity of key regulators of adipogenesis. The purpose of this research is to find genes among the WNT/${\beta}$-catenin pathway which regulate adipogenesis by using small interfering (si) RNA and to find the association of single nucleotide polymorphisms (SNPs) of the gene with serum triglyceride levels in the human population. To elucidate the effects of ${\beta}$-catenin siRNA on adipogenesis key factors, PPAR${\gamma}$ and C/EBP${\alpha}$, we performed real-time PCR and western blotting experiments for the analyses of mRNA and protein levels. It was found that the siRNA-mediated knockdown of ${\beta}$-catenin upregulates adipogenesis key factors. However, upstream regulators of the WNT/${\beta}$-catenin pathway, such as DVL2 and LRP6, had no significant effects compared to ${\beta}$-catenin. These results indicate that ${\beta}$-catenin is a candidate gene for human fat accumulation. In general, serum triglyceride level is a good indicator of fat accumulation in humans. According to statistical analyses of the association between serum triglyceride level and SNPs of ${\beta}$-catenin, -10,288 C>T SNP (rs7630377) in the promoter region was significantly associated with serum triglyceride levels (p<0.05) in 290 Korean subjects. On the other hand, serum cholesterol levels were not significantly associated with SNPs of the ${\beta}$-catenin gene. The results of this study showed that ${\beta}$-catenin is associated with fat accumulation both in vitro and in the human population.