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Melissa V Gammons, Trevor J Rutherford, Zachary Steinhart, Stephane Angers, Mariann Bienz
Dishevelled (DVL) assembles Wnt signalosomes through dynamic head-to-tail polymerisation by means of its DIX domain. It thus transduces Wnt signals to cytoplasmic effectors including β-catenin, to control cell fates during normal development, tissue homeostasis and also in cancer. To date, most functional studies of Dishevelled relied on its Wnt-independent signalling activity resulting from overexpression, which is sufficient to trigger polymerisation, bypassing the requirement for Wnt signals. Here, we generate a human cell line devoid of endogenous Dishevelled (DVL1- DVL3), which lacks Wnt signal transduction to β-catenin...
October 15, 2016: Journal of Cell Science
Chi Huang, Younan Wang, Hao Fan, Xiang Ma, Ran Tang, Xiangkun Huan, Yi Zhu, Zekuan Xu, Hao Xu, Li Yang
PURPOSE: Disheveled-binding antagonist of beta-catenin 1 (DACT1) is involved in tumorigenesis through influencing cell apoptosis and proliferation. We aimed to investigate the effect of three tag single-nucleotide polymorphisms (SNPs) in DACT1 (rs863091 C>T, rs17832998 C>T, and rs167481 C>T) on the occurrence of gastric cancer (GC), their association with specific clinical characteristics, and consideration of the functional relevance of GC-related SNPs. SUBJECTS AND METHODS: In this hospital-based case-control study, the genotypes were acquired using the TaqMan-MGB method consisting of 602 cases and 602 controls...
2016: OncoTargets and Therapy
Daniele Pereira Jardim, Paula Cristina Eiras Poço, Alexandre Holthausen Campos
Chronic kidney disease (CKD) is a worldwide public health problem that affects millions of men and women of all ages and racial groups. Loss of mesangial cells (MC) represents an early common feature in the pathogenesis of CKD. Transforming growth factor-β1 (TGF-β1) is a key inducer of kidney damage and triggers several pathological changes in renal cells, notably MC apoptosis. However, the mechanism of MC apoptosis induced by TGF-β1 remains elusive. Here we demonstrate for the first time a novel regulatory pathway in which the disheveled-binding antagonist of beta-catenin 1 (Dact1) gene is upregulated by TGF-β1, inducing MC apoptosis...
October 7, 2016: Journal of Cellular Physiology
Shuyuan Chen, Qin Zhang, Baoling Bai, Shengrong Ouyang, Yihua Bao, Huili Li, Ting Zhang
Dishevelled (DVL/Dvl) genes play roles in canonical and noncanonical Wnt signaling, both of which are essential in neural tube closing and are involved in balancing neural progenitor growth and differentiation, or neuroepithelial cell polarity, respectively. In mouse Dvl haploinsufficiency leads to neural tube defects (NTDs), which represent the second most common birth defects. However, DVL genes' genetic contributions in human NTDs are modest. We sought to explore the molecular impact on such genes in human NTDs in a Han Chinese cohort...
October 6, 2016: Molecular Neurobiology
Melissa V Gammons, Miha Renko, Christopher M Johnson, Trevor J Rutherford, Mariann Bienz
Extracellular signals are often transduced by dynamic signaling complexes ("signalosomes") assembled by oligomerizing hub proteins following their recruitment to signal-activated transmembrane receptors. A paradigm is the Wnt signalosome, which is assembled by Dishevelled via reversible head-to-tail polymerization by its DIX domain. Its activity causes stabilization of β-catenin, a Wnt effector with pivotal roles in animal development and cancer. How Wnt triggers signalosome assembly is unknown. Here, we use structural analysis, as well as biophysical and cell-based assays, to show that the DEP domain of Dishevelled undergoes a conformational switch, from monomeric to swapped dimer, to trigger DIX-dependent polymerization and signaling to β-catenin...
October 6, 2016: Molecular Cell
Dora Fabijanovic, Iris Zunic, Tamara Nikuseva Martic, Faruk Skenderi, Ljiljana Serman, Semir Vranic
Germ cell tumors of the testis are a heterogeneous group of neoplasms that affect male adolescents and young adults. Wnt signaling pathway components have been shown to be actively involved in normal and malignant germ cell differentiation and progression. In this study, we aimed to explore the expression patterns of the secreted frizzled-related protein (SFRP) and Disheveled protein family (DVL) in a subset of testicular germ cell tumors. Eighty-five formalin-fixed, paraffin-embedded tissue samples of the primary germ cell tumors of the testis were stained against SFRP1, SFRP3, DVL1, and DVL2 proteins using immunohistochemistry...
November 2016: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
Min Liu, Yajuan Li, Aiguo Liu, Ruifeng Li, Ying Su, Juan Du, Cheng Li, Alan Jian Zhu
Wingless (Wg)/Wnt signaling is conserved in all metazoan animals and plays critical roles in development. The Wg/Wnt morphogen reception is essential for signal activation, whose activity is mediated through the receptor complex and a scaffold protein Dishevelled (Dsh). We report here that the exon junction complex (EJC) activity is indispensable for Wg signaling by maintaining an appropriate level of Dsh protein for Wg ligand reception in Drosophila. Transcriptome analyses in Drosophila wing imaginal discs indicate that the EJC controls the splicing of the cell polarity gene discs large 1 (dlg1), whose coding protein directly interacts with Dsh...
2016: ELife
Kar Men Mah, Douglas W Houston, Joshua A Weiner
The 22 γ-Protocadherin (γ-Pcdh) adhesion molecules encoded by the Pcdhg gene cluster play critical roles in nervous system development, including regulation of dendrite arborisation, neuronal survival, and synaptogenesis. Recently, they have been implicated in suppression of tumour cell growth by inhibition of canonical Wnt signalling, though the mechanisms through which this occurs remain unknown. Here, we show differential regulation of Wnt signalling by individual γ-Pcdhs: The C3 isoform uniquely inhibits the pathway, whilst 13 other isoforms upregulate signalling...
2016: Scientific Reports
Haim Belinson, Adam K Savage, Douglas Fadrosh, Yien-Ming Kuo, Din Lin, Ricardo Valladares, Ysbrand Nusse, Anthony Wynshaw-Boris, Susan V Lynch, Richard M Locksley, Ophir D Klein
Homeostasis of the gastrointestinal (GI) tract is controlled by complex interactions between epithelial and immune cells and the resident microbiota. Here, we studied the role of Wnt signaling in GI homeostasis using Disheveled 1 knockout (Dvl1 (-/-)) mice, which display an increase in whole gut transit time. This phenotype is associated with a reduction and mislocalization of Paneth cells and an increase in CD8(+) T cells in the lamina propria. Bone marrow chimera experiments demonstrated that GI dysfunction requires abnormalities in both epithelial and immune cells...
July 7, 2016: JCI Insight
Weijie Wu, Qingqing Liu, Yuxi Liu, Zhaohui Yu, Youhua Wang
Dixdc1 (DIX domain containing-1), the mammalian homolog of Ccd1 (Coiled-coil-Dishevelled-Axin1), is a protein containing a coiled-coil domain and a Dishevelled-Axin (DIX) domain. As a novel component of the Wnt pathway, Dixdc1 has been reported to be able to promote neural progenitor proliferation and neuronal differentiation via Wnt/β-catenin signaling. But there still remains something unknown about Dixdc1 distribution and functions in the lesion and regeneration of the peripheral nervous system (PNS), so we tried to investigate dynamic changes of Dixdc1 expression in a rat sciatic nerve crush (SNC) model in this study...
September 16, 2016: Biochemical and Biophysical Research Communications
Xiaohong Li, Ying Xiao, Shaoqing Fan, Mingbing Xiao, Xiaotong Wang, Xiaolin Zhu, Xudong Chen, Chunsun Li, Guijuan Zong, Guoxiong Zhou, Chunhua Wan
DIX domain containing 1 (DIXDC1), a protein containing a coiled-coil domain and a Dishevelled-Axin (DIX) domain, is involved in the progression of multiple cancers. However, the role of DIXDC1 in human pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this study, we investigated the role and prognostic value of DIXDC1 in the development of human PDAC. Western blot analysis revealed that DIXDC1 was highly expressed in PDAC tissues and cell lines. Immunohistochemistry on 165 paraffin-embedded sections showed that high expression of DIXDC1 was significantly correlated with tumor size (P=...
August 3, 2016: Human Pathology
Igor Cervenka, Jana Valnohova, Ondrej Bernatik, Jakub Harnos, Matej Radsetoulal, Katerina Sedova, Katerina Hanakova, David Potesil, Miroslava Sedlackova, Alena Salasova, Zachary Steinhart, Stephane Angers, Gunnar Schulte, Ales Hampl, Zbynek Zdrahal, Vitezslav Bryja
Dishevelled (DVL) is a key scaffolding protein and a branching point in Wnt signaling pathways. Here, we present conclusive evidence that DVL regulates the centrosomal cycle. We demonstrate that DVL dishevelled and axin (DIX) domain, but not DIX domain-mediated multimerization, is essential for DVL's centrosomal localization. DVL accumulates during the cell cycle and associates with NIMA-related kinase 2 (NEK2), which is able to phosphorylate DVL at a multitude of residues, as detected by a set of novel phospho-specific antibodies...
August 16, 2016: Proceedings of the National Academy of Sciences of the United States of America
Senjun Zhou, Jiliang Shen, Shuang Lin, Xiaolong Liu, Ming Xu, Liang Shi, Xianfa Wang, Xiujun Cai
Dishevelled-Axin domain containing 1 (DIXDC1) is a DIX (Dishevelled-Axin) domain possessing protein that acts as a positive regulator of the Wnt pathway. Although DIXDC1 has been investigated in several cancers, it has not yet been studied in human hepatocellular carcinoma (HCC). The purpose of the current study was to investigate the expression pattern of DIXDC1 and assess the clinical significance of DIXDC1 expression in HCC patients. Data containing three independent investigations from Oncomine database demonstrated that DIXDC1 mRNA was downregulated in HCC compared with matched non-cancerous tissues...
July 28, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Elisa Arthofer, Belma Hot, Julian Petersen, Katerina Strakova, Stefan Jäger, Manuel Grundmann, Evi Kostenis, J Silvio Gutkind, Gunnar Schulte
Frizzleds (FZDs) are unconventional G protein-coupled receptors that belong to the class Frizzled. They are bound and activated by the Wingless/Int-1 lipoglycoprotein (WNT) family of secreted lipoglycoproteins. To date, mechanisms of signal initiation and FZD-G protein coupling remain poorly understood. Previously, we showed that FZD6 assembles with Gαi1/Gαq (but not with Gαs, Gαo and Ga12/13), and that these inactive-state complexes are dissociated by WNTs and regulated by the phosphoprotein Dishevelled (DVL)...
October 2016: Molecular Pharmacology
Ke Luo, Xiuhui Gu, Jing Liu, Guodan Zeng, Liaotian Peng, Houyi Huang, Mengju Jiang, Ping Yang, Minhui Li, Yuhan Yang, Yuanyuan Wang, Quekun Peng, Li Zhu, Kun Zhang
Cisplatin (CDDP) is currently recommended as the front-line chemotherapeutic agent for lung cancer. However, the resistance to cisplatin is widespread in patients with advanced lung cancer, and the molecular mechanism of such resistance remains incompletely understood. Disheveled (DVL), a key mediator of Wnt/β-catenin, has been linked to cancer progression, while the role of DVL in cancer drug resistance is not clear. Here, we found that DVL2 was over-expressed in cisplatin-resistant human lung cancer cells A549/CDDP compared to the parental A549 cells...
September 10, 2016: Experimental Cell Research
Markus Winter, Dmitri Lodygin, Berlinda Verdoodt, Heiko Hermeking
The p53-inducible cell cycle regulator 14-3-3σ exhibits tumor suppressive functions and is highly expressed in differentiating layers of the epidermis and hair follicles. 14-3-3σ/SFN/stratifin is frequently silenced in human epithelial cancers, and experimental down-regulation of 14-3-3σ expression immortalizes primary human keratinocytes. In the repeated-epilation (ER) mouse model, a heterozygous nonsense mutation of 14-3-3σ causes repeated hair-loss, hyper-proliferative epidermis, and spontaneous development of papillomas and squamous cell carcinomas in aging mice...
July 7, 2016: Oncotarget
Liqun Yuan, Shu Hu, Zeynep Okray, Xi Ren, Natalie De Geest, Annelies Claeys, Jiekun Yan, Eric Bellefroid, Bassem A Hassan, Xiao-Jiang Quan
The neurogenin (Ngn) transcription factors control early neurogenesis and neurite outgrowth in mammalian cortex. In contrast to their proneural activity, their function in neurite growth is poorly understood. Drosophila has a single predicted Ngn homolog, Tap, of unknown function. Here we show that Tap is not a proneural protein in Drosophila but is required for proper axonal growth and guidance of neurons of the mushroom body, a neuropile required for associative learning and memory. Genetic and expression analyses suggest that Tap inhibits excessive axonal growth by fine regulation of the levels of the Wnt signaling adaptor protein Dishevelled...
August 1, 2016: Development
Lindsay K Kelly, Jun Wu, Wang A Yanfeng, Marek Mlodzik
Epithelial tissues are polarized along two axes. In addition to apical-basal polarity, they are often polarized within the plane of the epithelium, so-called Planar Cell Polarity (PCP). PCP depends upon Wnt/Frizzled (Fz) signaling factors, including Fz itself and Van Gogh (Vang/Vangl). We sought to understand how Vang interaction with other core PCP factors affects Vang function. We find that Fz induces Vang phosphorylation in a cell-autonomous manner. Vang phosphorylation occurs on conserved N-terminal serine/threonine residues, is mediated by CK1ε/Dco, and is critical for polarized membrane localization of Vang and other PCP proteins...
July 12, 2016: Cell Reports
Shinya Ohata, Arturo Alvarez-Buylla
Cerebrospinal fluid (CSF) continuously flows through the cerebral ventricles, a process essential for brain homeostasis. Multiciliated ependymal (E1) cells line the walls of the ventricles and contribute importantly to CSF flow through ciliary beating. Key to this function is the rotational and translational planar cell polarity (PCP) of E1 cells. Defects in the PCP of E1 cells can result in abnormal CSF accumulation and hydrocephalus. Here, we integrate recent data on the roles of early CSF flow in the embryonic ventricles, PCP regulators (e...
August 2016: Trends in Neurosciences
Min Kyu Yum, Jong-Seol Kang, Al-Eum Lee, Young-Woo Jo, Ji-Yun Seo, Hyun-A Kim, Yoon-Young Kim, Jinwoo Seong, Eun Byul Lee, Ji-Hoon Kim, Jung Min Han, Sunghoon Kim, Young-Yun Kong
Wnt/β-catenin (CTNNB1) signaling is crucial for the proliferation and maintenance of intestinal stem cells (ISC), but excessive activation leads to ISC expansion and eventually colorectal cancer. Thus, negative regulators are required to maintain optimal levels of Wnt/β-catenin signaling. Aminoacyl-tRNA synthetase-interacting multifunctional proteins (AIMP) function in protein synthesis, but have also been implicated in signaling cascades affecting angiogenesis, immunity, and apoptosis. In this study, we investigated the relationship between AIMP2 and Wnt/β-catenin signaling in a murine model of intestinal homeostasis and tumorigenesis...
August 1, 2016: Cancer Research
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