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Juan Wang, Yuki Shibayama, Daisuke Nakano, Hirofumi Hitomi, Akira Nishiyama
OBJECTIVE: Constitutive activation of Wnt/β-catenin pathway plays an important role in the pathogenesis of colon cancer; however, recent studies have also indicated that elevated Wnt levels are essential. In the present study, we investigated the potential role of (pro) renin receptor in the pathophysiology of colon cancer. DESIGN AND METHOD: (P) RR expression in human colon tissues was measured by immunohistochemistry and Western blot analysis. Human colon cancer cell lines DLD-1 with adenomatous polyposis coli (APC) truncated mutation, and HCT116 withβ-catenin activating mutation, were transfected with scramble siRNA and siRNA against (pro) renin receptor...
September 2016: Journal of Hypertension
Elsa Perrody, Laurence Abrami, Michal Feldman, Beatrice Kunz, Sylvie Urbé, Gisou van der Goot
Many membrane proteins fold inefficiently and require the help of enzymes and chaperones. Here we reveal a novel folding assistance system that operates on membrane proteins from the cytosolic side of the endoplasmic reticulum (ER). We show that folding of the Wnt signaling coreceptor LRP6 is promoted by ubiquitination of a specific lysine, retaining it in the ER while avoiding degradation. Subsequent ER exit requires removal of ubiquitin from this lysine by the deubiquitinating enzyme USP19. This ubiquitination-deubiquitination is conceptually reminiscent of the glucosylation-deglucosylation occurring in the ER lumen during the calnexin/calreticulin folding cycle...
October 18, 2016: ELife
Hailin Yang, Jinbo Dong, Wei Xiong, Zhong Fang, Hanfeng Guan, Feng Li
Sclerostin/SOST is a robust negative regulator of bone formation. Loss-of-function mutations of the sclerostin gene (SOST) cause sclerosteosis and Van Buchem disease characterized by bone overgrowth. Mediated by myocyte enhancer factor 2 (MEF2) transcription factors, parathyroid hormone (PTH) suppresses SOST expression through formation of complexes of parathyroid hormone-parathyroid hormone-related peptide receptor 1 (PTH1R) and lipoprotein receptor-related protein 6 (LRP6). N-cadherin has been shown to negatively regulate Wnt/β-catenin and PTH induced, protein kinase-dependent β-catenin signaling...
October 10, 2016: Annals of the New York Academy of Sciences
Alana M Chin, Yu-Hwai Tsai, Stacy R Finkbeiner, Melinda S Nagy, Emily M Walker, Nicole J Ethen, Bart O Williams, Michele A Battle, Jason R Spence
Much of our understanding about how intestinal stem and progenitor cells are regulated comes from studying the late fetal stages of development and the adult intestine. In this light, little is known about intestine development prior to the formation of stereotypical villus structures with columnar epithelium, a stage when the epithelium is pseudostratified and appears to be a relatively uniform population of progenitor cells with high proliferative capacity. Here, we investigated a role for WNT/β-CATENIN signaling during the pseudostratified stages of development (E13...
October 6, 2016: Stem Cell Reports
Peter Broderick, Sara E Dobbins, Daniel Chubb, Ben Kinnersley, Malcolm G Dunlop, Ian Tomlinson, Richard S Houlston
High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1, TP53, BUB1, BUB3, LRP6, and PTPN12 have been recently proposed to increase CRC risk. We attempted to validate the association between variants in these genes and development of CRC in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC (controls). All cases were diagnosed at an age of 55 years or younger and did not carry mutations in an established CRC predisposition gene...
October 3, 2016: Gastroenterology
Nora Bengoa-Vergniory, Irantzu Gorroño-Etxebarria, Inmaculada López-Sánchez, Michele Marra, Pierluigi Di Chiaro, Robert Kypta
Wnt proteins preferentially activate either β-catenin-dependent or β-catenin-independent signals, but the activity of a particular Wnt also depends on cellular context and receptor availability. We previously reported that Wnt-3a induces neural differentiation of human embryonic stem cell-derived neural stem cells (NSCs) in a β-catenin-independent manner by activating a signal involving JNK and the AP-1 family member ATF-2. Here, we report the results of a gene silencing approach to identify the Wnt receptors that mediate this response to Wnt-3a...
October 5, 2016: Molecular Neurobiology
Rafael Escate, Teresa Padro, Maria Borrell-Pages, Rosa Suades, Rosa Aledo, Pedro Mata, Lina Badimon
Familial hypercholesterolaemia (FH) is a major risk for premature coronary heart disease due to severe long-life exposure to high LDL levels. Accumulation of LDL in the vascular wall triggers atherosclerosis with activation of the innate immunity system. Here, we have investigated (i) gene expression of LDLR and LRPs in peripheral blood cells (PBLs) and in differentiated macrophages of young FH-patients; and (ii) whether macrophage from FH patients have a differential response when exposed to high levels of atherogenic LDL...
September 29, 2016: Journal of Cellular and Molecular Medicine
Juan Wang, Yuki Shibayama, Daisuke Nakano, Hirofumi Hitomi, Akira Nishiyama
OBJECTIVE: Constitutive activation of Wnt/β-catenin pathway plays an important role in the pathogenesis of colon cancer; however, recent studies have also indicated that elevated Wnt levels are essential. In the present study, we investigated the potential role of (pro) renin receptor in the pathophysiology of colon cancer. DESIGN AND METHOD: (P) RR expression in human colon tissues was measured by immunohistochemistry and Western blot analysis. Human colon cancer cell lines DLD-1 with adenomatous polyposis coli (APC) truncated mutation, and HCT116 withβ-catenin activating mutation, were transfected with scramble siRNA and siRNA against (pro) renin receptor...
September 2016: Journal of Hypertension
Travis A Burgers, Juan F Vivanco, Juraj Zahatnansky, Andrew J Vander Moren, James J Mason, Bart O Williams
Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/β-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density...
2016: Bone Research
Miso Jeon, Naimur Rahman, Yong-Sik Kim
The canonical Wnt/β-catenin signaling not only features in many developmental processes but also recently emerged as an attractive negative regulator of differentiation of preadipocytes into adipocytes. Here, we show that β-catenin signaling plays a distinct role in methyl gallate (MG)-mediated inhibition of 3T3-L1 adipocytes differentiation. We found that the expression of β-catenin decreased after adipogenic hormonal induction, whereas incubation of the differentiating cells with a physiological concentration of MG during adipogenic hormonal induction significantly prevented β-catenin degradation by activating Wnt signaling components such as Wnt1, Wnt10b, Fzd1, Fzd2, Lrp5, Lrp6, Dvl1, and Dvl2...
October 7, 2016: Biochemical and Biophysical Research Communications
Xiaomo Jiang, Feng Cong
Wnt pathways are critical for embryonic development and adult tissue homeostasis in all multicellular animals. Many regulatory mechanisms exist to control proper signaling output. Recent studies suggest that cell surface Wnt receptor level is controlled by ubiquitination, and serve as a critical regulatory point of Wnt pathway activity as it determines the responsiveness of cells to Wnt signal. Here, we describe flow cytometry, cell surface protein biotinylation, and immunofluorescence pulse-chase methods to probe the surface expression, ubiquitination, and internalization of the Wnt receptors FZD and LRP6...
2016: Methods in Molecular Biology
Luc Chouinard, Melanie Felx, Nacera Mellal, Aurora Varela, Peter Mann, Jacquelin Jolette, Rana Samadfam, Susan Y Smith, Kathrin Locher, Sabina Buntich, Michael S Ominsky, Ian Pyrah, Rogely Waite Boyce
Romosozumab is a humanized immunoglobulin G2 monoclonal antibody that binds and blocks the action of sclerostin, a protein secreted by the osteocyte and an extracellular inhibitor of canonical Wnt signaling. Blockade of sclerostin binding to low-density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6) allows Wnt ligands to activate canonical Wnt signaling in bone, increasing bone formation and decreasing bone resorption, making sclerostin an attractive target for osteoporosis therapy. Because romosozumab is a bone-forming agent and an activator of canonical Wnt signaling, questions have arisen regarding a potential carcinogenic risk...
August 26, 2016: Regulatory Toxicology and Pharmacology: RTP
Sergio P Acebron, Christof Niehrs
Wnt/LRP6 signaling is best known for the β-catenin-dependent regulation of target genes. However, pathway branches have recently emerged, including Wnt/STOP signaling, which act independently of β-catenin and transcription. We review here the molecular mechanisms underlying β-catenin-independent Wnt/LRP6 signaling cascades and their implications for cell biology, development, and physiology.
August 24, 2016: Trends in Cell Biology
V Boschert, C Frisch, J W Back, K van Pee, S E Weidauer, E-M Muth, P Schmieder, M Beerbaum, A Knappik, P Timmerman, T D Mueller
The glycoprotein sclerostin has been identified as a negative regulator of bone growth. It exerts its function by interacting with the Wnt co-receptor LRP5/6, blocks the binding of Wnt factors and thereby inhibits Wnt signalling. Neutralizing anti-sclerostin antibodies are able to restore Wnt activity and enhance bone growth thereby presenting a new osteoanabolic therapy approach for diseases such as osteoporosis. We have generated various Fab antibodies against human and murine sclerostin using a phage display set-up...
August 2016: Open Biology
Da Jing, Mingming Zhai, Shichao Tong, Fei Xu, Jing Cai, Guanghao Shen, Yan Wu, Xiaokang Li, Kangning Xie, Juan Liu, Qiaoling Xu, Erping Luo
Treatment of osseous defects remains a formidable clinical challenge. Porous titanium alloys (pTi) have been emerging as ideal endosseous implants due to the excellent biocompatibility and structural properties, whereas inadequate osseointegration poses risks for unreliable long-term implant stability. Substantial evidence indicates that pulsed electromagnetic fields (PEMF), as a safe noninvasive method, inhibit osteopenia/osteoporosis experimentally and clinically. We herein investigated the efficiency and potential mechanisms of PEMF on osteogenesis and osseointegration of pTi in vitro and in vivo...
2016: Scientific Reports
W L Zhang, W J Ma, S Chen, X Z Wu, H R Zhang, J H Zhang
OBJECTIVE: To explore the molecular mechanisms of resistance to phosphatidyl inositol 3-kinase (PI3K) inhibitors in triple-negative breast cancer (TNBC) cells. METHODS: HCC70 cells (TNBC) were transfected with siFZD7, siWANT5B or siGSK3 using lipofectamine 2000 transfection reagent. The expression levels of key proteins of WNT/β-catenin and PI3K/AKT/mTOR pathways were determined by Western blot analysis. After HCC70, MCF-7 (ER-positive) and SK-BR3 (HER2-positive) cells were treated with PI3K/AKT/mTOR inhibitors, the inhibition rates of cell proliferation were measured by MTT assay, and half maximal inhibitory concentrations (IC50) were calculated...
August 2016: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
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
Matthias Zebisch, Verity A Jackson, Yuguang Zhao, E Yvonne Jones
Kremen 1 and 2 have been identified as co-receptors for Dickkopf (Dkk) proteins, hallmark secreted antagonists of canonical Wnt signaling. We present here three crystal structures of the ectodomain of human Kremen1 (KRM1ECD) at resolutions between 1.9 and 3.2 Å. KRM1ECD emerges as a rigid molecule with tight interactions stabilizing a triangular arrangement of its Kringle, WSC, and CUB structural domains. The structures reveal an unpredicted homology of the WSC domain to hepatocyte growth factor. We further report the general architecture of the ternary complex formed by the Wnt co-receptor Lrp5/6, Dkk, and Krm, determined from a low-resolution complex crystal structure between β-propeller/EGF repeats (PE) 3 and 4 of the Wnt co-receptor LRP6 (LRP6PE3PE4), the cysteine-rich domain 2 (CRD2) of DKK1, and KRM1ECD...
September 6, 2016: Structure
Jian Guo, Yang Li, Yi-Hong Ren, Zhijun Sun, Jie Dong, Han Yan, Yujun Xu, Dao Wen Wang, Gu-Yan Zheng, Jie Du, Xiao-Li Tian
Mutations in the genes low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) and myocyte enhancer factor 2A (MEF2A) were reported in families with coronary artery disease (CAD). We intend to determine the mutational spectrum of these genes among hyperlipidemic and normolipidemic CAD families. Forty probands with early-onset CAD were recruited from 19 hyperlipidemic and 21 normolipidemic Chinese families. We sequenced all exons and intron-exon boundaries of LRP6 and MEF2A, and found a novel heterozygous variant in LRP6 from a proband with normolipidemic CAD...
2016: International Journal of Molecular Sciences
Heather Jackson, David Granger, Gavin Jones, Louisa Anderson, Sarah Friel, Daniel Rycroft, William Fieles, James Tunstead, Michael Steward, Trevor Wattam, Adam Walker, Jeremy Griggs, Muhammad Al-Hajj, Christopher Shelton
UNLABELLED: Aberrant WNT signaling is associated with the formation and growth of numerous human cancer types. The low-density lipoprotein receptor-related protein 6 (LRP6) is the least redundant component of the WNT receptor complex with two independent WNT ligand-binding sites. Using domain antibody (dAb) technology, a bispecific antibody (GSK3178022) to LRP6 was identified that is capable of blocking stimulation in the presence of a range of WNT and R-spondin (RSPO) ligands in vitro GSK3178022 was also efficacious in reducing WNT target gene expression in vivo, in both cancer cell line and patient-derived xenograft models, and delays tumor growth in a patient-derived RSPO fusion model of colorectal cancer...
September 2016: Molecular Cancer Research: MCR
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