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Rspo3

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https://www.readbyqxmd.com/read/29769720/rspo2-inhibition-of-rnf43-and-znrf3-governs-limb-development-independently-of-lgr4-5-6
#1
Emmanuelle Szenker-Ravi, Umut Altunoglu, Marc Leushacke, Célia Bosso-Lefèvre, Muznah Khatoo, Hong Thi Tran, Thomas Naert, Rivka Noelanders, Amin Hajamohideen, Claire Beneteau, Sergio B de Sousa, Birsen Karaman, Xenia Latypova, Seher Başaran, Esra Börklü Yücel, Thong Teck Tan, Lena Vlaeminck, Shalini S Nayak, Anju Shukla, Katta Mohan Girisha, Cédric Le Caignec, Natalia Soshnikova, Zehra Oya Uyguner, Kris Vleminckx, Nick Barker, Hülya Kayserili, Bruno Reversade
The four R-spondin secreted ligands (RSPO1-RSPO4) act via their cognate LGR4, LGR5 and LGR6 receptors to amplify WNT signalling1-3 . Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs. Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity. Unexpectedly, however, the triple and ubiquitous knockout of Lgr4, Lgr5 and Lgr6 in mice did not recapitulate the known Rspo2 or Rspo3 loss-of-function phenotypes...
May 16, 2018: Nature
https://www.readbyqxmd.com/read/29752411/differential-activities-and-mechanisms-of-the-four-r-spondins-in-potentiating-wnt-%C3%AE-catenin-signaling
#2
Soohyun Park, Jie Cui, Wangsheng A Yu, Ling Wu, Kendra Carmon, Qingyun J Liu
The four R-spondins (RSPO1-4) strongly potentiate Wnt signaling and play critical roles in normal development, adult stem cell survival, and cancer development and aggressiveness. All four RSPOs have been suggested to potentiate Wnt signaling by binding to three related receptors, i.e., leucine-rich repeat containing, G protein-coupled receptors 4, 5 and 6 (LGR4/5/6), and then inducing the clearance of two E3 ubiquitin ligases (RNF43 and ZNRF3) that otherwise would ubiquitinate Wnt receptors for degradation...
May 11, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29748375/r-spondin3-is-associated-with-basal-progenitor-behavior-in-normal-and-tumor-mammary-cells
#3
Johanna Melisa Tocci, Carla María Felcher, Martín E García Solá, María Victoria Goddio, María Noel Zimberlin, Natalia Rubinstein, Anabella Srebrow, Omar Adrián Coso, Martín C Abba, Roberto P Meiss, Edith C Kordon
R-spondin3 (RSPO3) is a member of a family of secreted proteins that enhance Wnt signaling pathways in diverse processes including cancer. However, the role of RSPO3 in mammary gland and breast cancer development remains unclear. In this study, we show that RSPO3 is expressed in the basal stem cell-enriched compartment of normal mouse mammary glands but is absent from committed mature luminal cells in which exogenous RSPO3 impairs lactogenic differentiation. RSPO3 knockdown in basal-like mouse mammary tumor cells reduced canonical Wnt signaling, epithelial-to-mesenchymal transition-like features, migration capacity, and tumor formation in vivo...
May 10, 2018: Cancer Research
https://www.readbyqxmd.com/read/29559533/-pdgfr%C3%AE-pericryptal-stromal-cells-are-the-critical-source-of-wnts-and-rspo3-for-murine-intestinal-stem-cells-in-vivo
#4
Gediminas Greicius, Zahra Kabiri, Kristmundur Sigmundsson, Chao Liang, Ralph Bunte, Manvendra K Singh, David M Virshup
Wnts and R-spondins (RSPOs) support intestinal homeostasis by regulating crypt cell proliferation and differentiation. Ex vivo, Wnts secreted by Paneth cells in organoids can regulate the proliferation and differentiation of Lgr5 -expressing intestinal stem cells. However, in vivo, Paneth cell and indeed all epithelial Wnt production is completely dispensable, and the cellular source of Wnts and RSPOs that maintain the intestinal stem-cell niche is not known. Here we investigated both the source and the functional role of stromal Wnts and RSPO3 in regulation of intestinal homeostasis...
March 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29555474/r-spondin3-lgr4-signaling-protects-hepatocytes-against-dmog-induced-hypoxia-reoxygenation-injury-through-activating-%C3%AE-catenin
#5
Shiying Liu, Yue Yin, Ruili Yu, Yin Li, Weizhen Zhang
BACKGROUND & AIMS: Leucine-rich repeat G-protein-coupled receptor 4 (LGR4) and its ligands R-spondin1-4 (Rspos) have been vastly investigated in embryonic development. The biological functions of Rspos-LGR4 system in liver remains largely unknown. Here, we explored whether it protects hepatocytes against hypoxia/reoxygenation (H/R) induced damage. METHODS: H/R injury was induced by dimethyloxalylglycine (DMOG) in AML12 cells and the effects of Rspo3 on cell proliferation and apoptosis were assessed...
March 16, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29405118/r-spondins-can-potentiate-wnt-signaling-without-lgrs
#6
Andres M Lebensohn, Rajat Rohatgi
The WNT signaling pathway regulates patterning and morphogenesis during development and promotes tissue renewal and regeneration in adults. The R-spondin (RSPO) family of four secreted proteins, RSPO1-4, amplifies target cell sensitivity to WNT ligands by increasing WNT receptor levels. Leucine-rich repeat-containing G-protein coupled receptors (LGRs) 4-6 are considered obligate high-affinity receptors for RSPOs. We discovered that RSPO2 and RSPO3, but not RSPO1 or RSPO4, can potentiate WNT/β-catenin signaling in the absence of all three LGRs...
February 6, 2018: ELife
https://www.readbyqxmd.com/read/29230809/the-rspo3-gene-as-genetic-markers-for-bone-mass-assessed-by-quantitative-ultrasound-in-a-population-of-young-adults
#7
María Correa-Rodríguez, Jacqueline Schmidt Rio-Valle, Blanca Rueda-Medina
Ultrasound bone mass measurement has been postulated as a valuable bone-health assessment tool for primary care. The aim of this study was to analyse the possible relationship between the SPTBN1, RSPO3, CCDC170, DKK1, GPATCH1, and TMEM135 genes, with calcaneal quantitative ultrasound (QUS) in a population of young adults. These genes were first associated with broadband ultrasound attenuation (BUA) in the GEFOS/GENOMOS study. A cross-sectional study was conducted on 575 individuals (mean age 20.41 ± 2...
December 12, 2017: Annals of Human Genetics
https://www.readbyqxmd.com/read/29181107/investigation-of-fusion-gene-expression-in-hct116-cells
#8
Yanmei Zhang, Juan Ren, Mengdie Fang, Xiaoju Wang
Colon cancer is the most common type of gastrointestinal cancer. A number of specific and sensitive biomarkers facilitate the diagnosis and monitoring of patients with colon cancer. Fusion genes are typically identified in cancer and a majority of the newly identified fusion genes are oncogenic in nature. Therefore, fusion genes are potential biomarkers and/or therapy targets in cancer. In the present study, the regulation of specific candidate fusion genes were investigated using Brother of the Regulator of Imprinted Sites (BORIS) in the HCT116 colon cancer cell line, which is a paralog of the fusion gene regulator CCCTC-binding factor (CTCF)...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29127379/rspo3-antagonism-inhibits-growth-and-tumorigenicity-in-colorectal-tumors-harboring-common-wnt-pathway-mutations
#9
Marcus M Fischer, V Pete Yeung, Fiore Cattaruzza, Rajaa Hussein, Wan-Ching Yen, Christopher Murriel, James W Evans, Gilbert O'Young, Alayne L Brunner, Min Wang, Jennifer Cain, Belinda Cancilla, Ann Kapoun, Timothy Hoey
Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway blockers exhibit potent combinatorial activity with taxanes to inhibit tumor growth. Here we show that RSPO3 antagonism synergizes with paclitaxel based chemotherapies in patient-derived xenograft models (PDX) with RSPO3 fusions and in tumors with common CRC mutations such as APC, β-catenin, or RNF43...
November 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29055915/search-for-genetic-modifiers-of-psc-time-to-increase-the-number-of-needles-in-the-haystack
#10
Marcin Krawczyk, Frank Lammert
Primary sclerosing cholangitis (PSC) belongs to the most obscure liver diseases. Patients with progressive PSC require liver transplantation as only therapeutic option. Previously several HLA- and non-HLA-associated PSC risk variants have been discovered, however their involvement in the development of PSC seems to be minor in comparison to environmental determinants. Lately, variant rs853974 at the RSPO3 gene locus has been shown to modulate the course of PSC. Here we briefly discuss the phenotypes related to this polymorphism and propose alternative directions of research that might help to identify new genetic modifiers of PSC progression...
November 2017: Annals of Hepatology
https://www.readbyqxmd.com/read/29048660/canonical-and-non-canonical-wnt-signaling-in-cancer-stem-cells-and-their-niches-cellular-heterogeneity-omics-reprogramming-targeted-therapy-and-tumor-plasticity-review
#11
Masaru Katoh
Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49)...
November 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28834739/coronary-artery-formation-is-driven-by-localized-expression-of-r-spondin3
#12
Fabio Da Silva, Ana Sofia Rocha, Fariba Jian Motamedi, Filippo Massa, Cem Basboga, Harris Morrison, Kay Dietrich Wagner, Andreas Schedl
Coronary arteries are essential to support the heart with oxygen, and coronary heart disease is one of the leading causes of death worldwide. The coronary arteries form at highly stereotyped locations and are derived from the primitive vascular plexus of the heart. How coronary arteries are remodeled and the signaling molecules that govern this process are poorly understood. Here, we have identified the Wnt-signaling modulator Rspo3 as a crucial regulator of coronary artery formation in the developing heart...
August 22, 2017: Cell Reports
https://www.readbyqxmd.com/read/28757432/genetic-risk-of-prediabetes-and-diabetes-development-in-chronic-myeloid-leukemia-patients-treated-with-nilotinib
#13
Bruno Martino, Corrado Mammì, Claudia Labate, Silvia Rodi, Domenica Ielo, Manuela Priolo, Maurizio Postorino, Giovanni Tripepi, Francesca Ronco, Carmelo Laganà, Caterina Musolino, Marianna Greco, Giorgio La Nasa, Giovanni Caocci
Impaired fasting glucose and type 2 diabetes represent adverse events in patients with chronic myeloid leukemia (CML) treated with the second generation tyrosine kinase inhibitor nilotinib. An unweighted genetic risk score (uGRS) for the prediction of insulin resistance, consisting of 10 multiple single-nucleotide polymorphisms, has been proposed. We evaluated uGRS predictivity in 61 CML patients treated with nilotinib. Patients were genotyped for IRS1, GRB14, ARL15, PPARG, PEPD, ANKRD55/MAP3K1, PDGFC, LYPLAL1, RSPO3, and FAM13A1 genes...
November 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28731148/molecular-genetics-and-targeted-therapy-of-wnt-related-human-diseases-review
#14
Masuko Katoh, Masaru Katoh
Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription...
September 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28695896/r-spondin-chromosome-rearrangements-drive-wnt-dependent-tumour-initiation-and-maintenance-in-the-intestine
#15
Teng Han, Emma M Schatoff, Charles Murphy, Maria Paz Zafra, John E Wilkinson, Olivier Elemento, Lukas E Dow
Defining the genetic drivers of cancer progression is a key in understanding disease biology and developing effective targeted therapies. Chromosome rearrangements are a common feature of human malignancies, but whether they represent bona fide cancer drivers and therapeutically actionable targets, requires functional testing. Here, we describe the generation of transgenic, inducible CRISPR-based mouse systems to engineer and study recurrent colon cancer-associated EIF3E-RSPO2 and PTPRK-RSPO3 chromosome rearrangements in vivo...
July 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/28673252/comparative-muscle-transcriptome-associated-with-carcass-traits-of-nellore-cattle
#16
COMPARATIVE STUDY
Bárbara Silva-Vignato, Luiz L Coutinho, Aline S M Cesar, Mirele D Poleti, Luciana C A Regitano, Júlio C C Balieiro
BACKGROUND: Commercial cuts yield is an important trait for beef production, which affects the final value of the products, but its direct determination is a challenging procedure to be implemented in practice. The measurement of ribeye area (REA) and backfat thickness (BFT) can be used as indirect measures of meat yield. REA and BFT are important traits studied in beef cattle due to their strong implication in technological (carcass yield) and nutritional characteristics of meat products, like the degree of muscularity and total body fat...
July 3, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28543708/comprehensive-characterization-of-rspo-fusions-in-colorectal-traditional-serrated-adenomas
#17
Shigeki Sekine, Reiko Ogawa, Taiki Hashimoto, Kojima Motohiro, Hiroshi Yoshida, Hirokazu Taniguchi, Yutaka Saito, Ohno Yasuhiro, Atsushi Ochiai, Nobuyoshi Hiraoka
AIMS: Traditional serrated adenoma (TSA) is a rare but distinct type of colorectal polyp. Our previous study showed that PTPRK-RSPO3 fusions are frequent and characteristic genetic alterations in TSAs. This study aimed to characterize comprehensively the prevalence and variability of RSPO fusions in colorectal TSAs. METHODS AND RESULTS: We examined RSPO expression and explored novel RSPO fusions in 129 TSAs, including 66 lesions analysed previously for WNT pathway gene mutations...
May 24, 2017: Histopathology
https://www.readbyqxmd.com/read/28472463/genome-wide-association-study-meta-analysis-for-quantitative-ultrasound-parameters-of-bone-identifies-five-novel-loci-for-broadband-ultrasound-attenuation
#18
Benjamin H Mullin, Jing Hua Zhao, Suzanne J Brown, John R B Perry, Jian'an Luan, Hou-Feng Zheng, Claudia Langenberg, Frank Dudbridge, Robert Scott, Nick J Wareham, Tim D Spector, J Brent Richards, John P Walsh, Scott G Wilson
Osteoporosis is a common and debilitating bone disease that is characterised by low bone mineral density, typically assessed using dual-energy X-ray absorptiometry. Quantitative ultrasound (QUS), commonly utilising the two parameters velocity of sound (VOS) and broadband ultrasound attenuation (BUA), is an alternative technology used to assess bone properties at peripheral skeletal sites. The genetic influence on the bone qualities assessed by QUS remains an under-studied area. We performed a comprehensive genome-wide association study (GWAS) including low-frequency variants (minor allele frequency ≥0...
July 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28336956/preclinical-development-of-a-humanized-neutralizing-antibody-targeting-hgf
#19
Hyori Kim, Sung Hee Hong, Jung Yong Kim, In-Chull Kim, Young-Whan Park, Song-Jae Lee, Seong-Won Song, Jung Ju Kim, Gunwoo Park, Tae Min Kim, Yun-Hee Kim, Jong Bae Park, Junho Chung, In-Hoo Kim
Hepatocyte growth factor (HGF) and its receptor, cMET, play critical roles in cell proliferation, angiogenesis and invasion in a wide variety of cancers. We therefore examined the anti-tumor activity of the humanized monoclonal anti-HGF antibody, YYB-101, in nude mice bearing human glioblastoma xenografts as a single agent or in combination with temozolomide. HGF neutralization, The extracellular signal-related kinases 1 and 2 (ERK1/2) phosphorylation, and HGF-induced scattering were assessed in HGF-expressing cell lines treated with YYB-101...
March 24, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28220828/rspo3-lgr4-regulates-osteogenic-differentiation-of-human-adipose-derived-stem-cells-via-erk-fgf-signalling
#20
Min Zhang, Ping Zhang, Yunsong Liu, Longwei Lv, Xiao Zhang, Hao Liu, Yongsheng Zhou
The four R-spondins (RSPOs) and their three related receptors, LGR4, 5 and 6, have emerged as a major ligand-receptor system with critical roles in development and stem cell survival. However, the exact roles of the RSPO-LGR system in osteogenesis remain largely unknown. In the present study, we showed that RSPO3-shRNA increased the osteogenic potential of human adipose-derived stem cells (hASCs) significantly. Mechanistically, we demonstrated that RSPO3 is a negative regulator of ERK/FGF signalling. We confirmed that inhibition of the ERK1/2 signalling pathway blocked osteogenic differentiation in hASCs, and the increased osteogenic capacity observed after RSPO3 knockdown in hASCs was reversed by inhibition of ERK signalling...
February 21, 2017: Scientific Reports
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