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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-canonical WNTs activate the planar cell polarity (PCP) pathway to induce cell motility and metastasis, while canonical WNTs activate the beta-catenin-TCF pathway to induce carcinogenesis. WNT11 gene at human chromosome 11q13.5 encodes non-canonical WNT11 protein, which is applicable for regenerative medicine of heart diseases. Here, we identified and characterized rat Wnt11 gene by using bioinformatics. Rat Wnt11 gene, consisting of five exons, was identified within AC120107.3 genome sequence. Rat Wnt11 (354 aa) was a secreted protein with 24 conserved Cys residues and five Asn-linked glycosylation sites. Rat Wnt11 showed 99.4%, 97.5%, 84.5% and 76.0% total-amino-acid identity with mouse Wnt11, human WNT11, chicken wnt11 and zebrafish wnt11, respectively. Comparative proteomics revealed that the number of Asn-linked glycosylation sites increased during molecular evolution of Wnt11 orthologs. Comparative genomics revealed that exon 1, but not 5'-flanking region, was well conserved between rat Wnt11 and human WNT11 genes. Although conserved transcription-factor-binding site was not identified within 5'-flanking region of rat Wnt11 and human WNT11 genes, Nkx2-5-binding site within exon 1 was evolutionarily conserved among mammalian Wnt11 orthologs. Because Nkx2-5 and Wnt11 are key regulators of heart development, Wnt11 was predicted as a target gene of Nkx2-5 transcription factor during cardiac myocyte differentiation. This is the first report on rat Wnt11 gene as well as on comparative genomics for Wnt11 orthologs.
Int J Mol Med 2005 May
PMID:Comparative genomics on Wnt11 gene. 1580 13

The Wnt signaling plays important roles in cell growth, differentiation, polarity formation, and neural development. In the canonical pathway, two DIX domain-containing proteins, Dishevelled (Dvl) and Axin, regulate the degradation of beta-catenin that activates Wnt target genes through TCF/LEF family transcription factors. Recently, we have isolated a third type of DIX domain-possessing protein, Coiled-coil-DIX1 (Ccd1). Ccd1 forms homomeric and heteromeric complexes with Dvl and Axin, and regulates the neural patterning in zebrafish embryos through Wnt pathway activation. Here, we report the isolation and characterization of mouse Ccd1. Fourteen putative mRNA isoforms are generated by different promoter usage and alternative splicing, and each isoform shows different expression patterns in various tissues. The predicted Ccd1 proteins are classified into three subtypes, and a novel form, termed Ccd1A, possesses an N-terminal calponin homology domain, suggesting an additional interaction of the isoform with actin or other proteins. When Ccd1 proteins were singularly expressed in Hela cells, they showed almost no activation of TCF-dependent reporter transcription on their own. However, when Dvl protein, at the level that did not activate Wnt pathway by itself, was co-expressed with Ccd1, the reporter transcription was greatly potentiated in Ccd1-dose-dependent manner. In addition, Ccd1- and Wnt3a-dependent activation of Wnt pathway was inhibited by Axin or a dominant negative Ccd1. These results indicate that mouse Ccd1 functions as a positive regulator of the Wnt/beta-catenin pathway. Furthermore, Ccd1 is highly expressed and co-localized with Wnt signaling molecules in the embryonic and adult brain, implicating the importance of Ccd1 in the Wnt-mediated neuronal development, plasticity, and remodeling.
Brain Res Mol Brain Res 2005 Apr 27
PMID:Identification and differential expression of multiple isoforms of mouse Coiled-coil-DIX1 (Ccd1), a positive regulator of Wnt signaling. 1585 80

The nuclear receptor superfamily expanded in at least two episodes: one early in metazoan evolution, the second within the vertebrate lineage. An exception to this pattern is the genome of the nematode Caenorhabditis elegans, which encodes more than 270 nuclear receptors, most of them highly divergent. We generated 128 cDNA sequences for 76 C. elegans nuclear receptors, confirming that these are active genes. Among these numerous receptors are 13 orthologues of nuclear receptors found in arthropods and/or vertebrates. We show that the supplementary nuclear receptors (supnrs) originated from an explosive burst of duplications of a unique orphan receptor, HNF4. This origin has specific implications for the role of ligand binding in the function and evolution of the nematode supplementary nuclear receptors. Moreover, the supplementary nuclear receptors include a group of very rapidly evolving genes found primarily on chromosome V. We propose a model of lineage-specific duplications from a chromosome on which duplication and substitution rates are highly increased. Our results provide a framework to study nuclear receptors in nematodes, as well as to consider the functional and evolutionary consequences of lineage-specific duplications.
J Mol Evol 2005 May
PMID:Explosive lineage-specific expansion of the orphan nuclear receptor HNF4 in nematodes. 1598 67

WNT family proteins activate the beta-catenin - TCF pathway to induce carcinogenesis through cell fate determination, and also activate the planar cell polarity (PCP) pathway to induce cell motility and metastasis. DKK1, DKK2, DKK3 and DKK4 are secreted-type WNT signaling modulators belonging to the Dickkopf family. Here, we identified and characterized rat Dkk2 and Dkk4 genes by using bioinformatics. Rat Dkk2 and Dkk4 genes, consisting of four exons, were located within AC120263.4 and AC109661.6 genome sequences, respectively. Rat Dkk2 gene encoded a 259-aa protein, showing 95.8% total-amino-acid identity with human DKK2. Rat Dkk4 gene encoded a 221-aa protein, showing 75.4% total-amino-acid identity with human DKK4. Mammalian Dkk family members were secreted proteins with two Cys-rich regions, each containing ten conserved Cys residues. Asn-linked glycosylation site at codon 52 was conserved among mammalian Dkk2 orthologs; however, Asn-linked glycosylation site was not identified among mammalian Dkk4 orthologs. Dkk2 proteins were more conserved than Dkk4 proteins, while Dkk4 promoters were more conserved than Dkk2 promoters. TATA-box was identified within Dkk2 and Dkk4 promoters. MYOD and triple TCF/LEF binding sites were conserved between human DKK4 promoter and rodent Dkk4 promoter. DKK2 mRNA was expressed in Ewing's sarcoma, and fetal heart. DKK4 mRNA was expressed in human embryonic stem (ES) cells differentiated to an early endodermal cell type, breast cancer, and diffuse type gastric cancer. DKK4 orthologs are implicated in the negative feed back mechanism of the WNT/beta-catenin signaling pathway (the canonical WNT signaling pathway).
Int J Mol Med 2005 Sep
PMID:Comparative genomics on DKK2 and DKK4 orthologs. 1607 58

FGF and WNT signaling pathways network together during embryogenesis and carcinogenesis. Among 22 FGF family members within human and rodents genomes, FGF20 orthologs are evolutionarily conserved targets of the WNT/beta-catenin signaling pathway. FGF8, FGF17, and FGF18 constitute one of FGF subfamilies. Here, comparative proteomics and comparative genomics analyses on FGF8, FGF17, and FGF18 orthologs were performed. Rat Fgf8 and Fgf17 genes, consisting of five exons, were located within AC096326.7 and AC097410.12 genome sequences, respectively. FGF8, FGF17, and FGF18 orthologs were FGF family members with the N-terminal signal peptide. Human FGF8 isoform F showed 90.6% total-amino-acid identity with rat Fgf8 (268 aa). Human FGF17 showed 98.6% total-amino-acid identity with rat Fgf17 (216 aa). Human FGF18 also showed 98.6 total-amino-acid identity with rat Fgf18. FBXW1 (betaTRCP1 or BTRC1)-FGF8-NPM3 locus at human chromosome 10q24.32, FBXW11 (betaTRCP2 or BTRC2)-FGF18-NPM1 locus at human chromosome 5q35.1, and FGF17-NPM2 locus at human chromosome 8p21.3 were paralogous regions within the human genome. FGF8 mRNA was expressed in DMSO-treated embryonic stem (ES) cells. FGF17 mRNA was expressed in ES cells differentiated to an early endodermal phenotype. FGF18 mRNA was expressed in fetal lung, fetal heart, lung carcinoid, colorectal cancer, and ovarian cancer. FGF18 promoter with double TCF/LEF binding sites rather than FGF8 promoter and FGF17 promoter was more conserved between human and rodents. These facts indicate that FGF18 orthologs were evolutionarily conserved targets of the WNT/beta-catenin signaling pathway.
Int J Mol Med 2005 Sep
PMID:Comparative genomics on FGF8, FGF17, and FGF18 orthologs. 1607 60

We have previously reported comparative genomics analyses on FGF3, FGF4, FGF6, FGF7, FGF8, FGF10, FGF11, FGF17, FGF18, FGF19, FGF20, FGF22 and FGF23 genes. Here, we performed comparative genomics analyses on FGF1, FGF2, FGF5, FGF9, FGF12, FGF13, FGF14, FGF16 and FGF21 genes, and further characterized the FGF16 gene. Chimpanzee FGF16, chicken fgf16, and zebrafish fgf16 genes were identified within NW_121938.1, NW_060344.1, and CR855117.3 genome sequences, respectively. Chimpanzee FGF16 (207 aa), chicken fgf16 (207 aa), and zebrafish fgf16 (203 aa) showed 100%, 89.9%, and 79.2% total amino-acid identity with human FGF16. Because FGF16, FGF9, and FGF20 constitute FGF subfamily without N-terminal signal peptide, we next searched for uncharacterized FGF9 or FGF20 orthologs. Zebrafish fgf9 gene was identified within BX927112.11 genome sequence, and chicken fgf20 gene within NW_060349.1 genome sequence. Although N-terminal part was divergent, middle and C-terminal parts were well conserved among vertebrate FGF16, FGF9 and FGF20 orthologs. Phylogenetic analyses revealed that zebrafish fgf9 and fgf20 were more related to each other than to their chicken or mammalian orthologs. TCF/LEF binding site and TATA box were well conserved among the human FGF16, rat Fgf16, and mouse Fgf16 promoters. Because nuclear complex consisting of TCF/LEF (TCF1, TCF3, TCF4 or LEF1), beta-catenin, PYGO (PYGO1 or PYGO2) and Legless (BCL9 or BCL9L) binds to the TCF/LEF-binding site to up-regulate WNT/beta-catenin target genes, FGF16 gene was characterized as the evolutionarily conserved target of the WNT/beta-catenin signaling pathway, just like FGF18 and FGF20 genes. These facts indicate that FGF16, FGF18 and FGF20 are pharmacogenomics targets in the field of oncology and regenerative medicine.
Int J Mol Med 2005 Nov
PMID:Comparative genomics on FGF16 orthologs. 1621 Dec 70

We cloned and characterized human WNT2B (WNT13) in 1996. Following our discovery of human WNT2B, others and we characterized mouse, rat, chicken and zebrafish WNT2B orthologs. Here, comparative integromics analyses on WNT2B and its clinical applications are reviewed. WNT2B-ST7L-CAPZA1 locus at human chromosome 1p13.2 and WNT2-ST7-CAPZA2 locus at human chromosome 7q31.2 are paralogous regions within the human genome. Two splicing variants occur from human WNT2B gene due to alternative promoters. WNT2B splicing variant 1 encodes secreted-type glycoprotein with WNT domain (WNT2B isoform 1), while WNT2B splicing variant 2 encodes transmembrane-type glycoprotein with WNT domain (WNT2B isoform 2). WNT2B splicing variant 2 is the evolutionarily conserved major transcript of human WNT2B gene. Mammalian WNT2B orthologs acquired the transmembrane domain and integrin-targeting RGD motif during vertebrate evolution. Human WNT2B isoform 2 and other vertebrate WNT2B orthologs are canonical WNTs to determine cell fate through the activation of beta-catenin/TCF signaling pathway and SNAIL/EMT signaling pathway. E box and CCAAT box are conserved within mammalian WNT2B promoters. WNT2B functions as the stem cell factor for neural or retinal progenitor cells during embryogenesis, and also for gastric cancer, esophageal cancer and skin basal cell carcinoma during carcinogenesis. Anti-WNT2B monoclonal antibody could be applied as selection marker of stem cells in the field of stem cell biology. Soluble WNT2B protein or small molecule WNT2B mimic compounds could be developed for stem cell expansion in the fields of tissue engineering and regenerative medicine. Anti-WNT2B monoclonal antibodies, WNT2B RNAi compounds, or small molecule WNT2B inhibitors could be developed as novel therapeutic agents for gastric cancer and esophageal cancer in the field of clinical oncology.
Int J Mol Med 2005 Dec
PMID:WNT2B: comparative integromics and clinical applications (Review). 1627 93

Ischemic preconditioning (IP) enhances vascular endothelial growth factor (VEGF), Bcl-2 and survivin expression after myocardial infarction (MI). Mechanisms of angiogenic and anti-apoptotic effects due to IP still remain unclear. The present study attempts to address whether GSK-3beta-beta-catenin signaling in turn interacts with T-cell transcription factor/lymphoid-enhancer binding factor (TCF/LEF) and regulates these genes in the ischemic preconditioned myocardium. In a rat MI model with permanent occlusion of left anterior descending coronary artery (LAD), IP (four cycles of 4-min of ischemia and 4-min of reperfusion) significantly phosphorylated and inhibited GSK-3beta and accumulated beta-catenin in the cytosol and nucleus. Wortmannin, a PI-3 kinase inhibitor, repressed this effect in our model. We examined whether pretreatment with GSK-3beta inhibitor lithium or SB216763, mimicked IP-mediated angiogenesis and cardioprotection. Lithium- or SB216763- treated rats revealed accumulation of cytosolic and nuclear beta-catenin. This was followed by increased TCF/LEF transcriptional activity and the upregulation of VEGF, Bcl-2 and survivin mRNA expression accompanied by reduction of apoptotic cardiomyocytes and endothelial cells and increased capillary density after MI. The results of this study demonstrate, first time that inhibition of GSK-3beta followed by accumulation of beta-catenin in the cytosol and nucleus has potent anti-apoptotic and angiogenic effects after MI and that the PI3-kinase/GSK-3beta/beta-catenin signaling pathway plays an important role in IP.
J Mol Cell Cardiol 2006 Jan
PMID:Glycogen synthase kinase-3beta/beta-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and survivin expression in rat ischemic preconditioned myocardium. 1628 8

An important link between Wnt binding at the cell surface and nuclear -catenin-TCF-dependent transcription has been made with the identification of kinases that promote the association of the Wnt receptor and -catenin turnover complexes. Surprisingly, the enzymes implicated had previously been suggested to inhibit rather than promote Wnt signaling.
Nat Struct Mol Biol 2006 Jan
PMID:Kinase cogs go forward and reverse in the Wnt signaling machine. 1639 16

WNT, FGF and Hedgehog signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. FGF16, FGF18, and FGF20 genes are targets of WNT-mediated TCF/LEF-beta-catenin-BCL9/BCL9L-PYGO transcriptional complex. SPROUTY (SPRY) and SPRED family genes encode inhibitors for receptor tyrosine kinase signaling cascades, such as those of FGF receptor family members and EGF receptor family members. Here, transcriptional regulation of SPRY1, SPRY2, SPRY3, SPRY4, SPRED1, SPRED2, and SPRED3 genes by WNT/beta-catenin signaling cascade was investigated by using bioinformatics and human intelligence (humint). Because double TCF/LEF-binding sites were identified within the 5'-promoter region of human SPRY4 gene, comparative genomics analyses on SPRY4 orthologs were further performed. SPRY4-FGF1 locus at human chromosome 5q31.3 and FGF2-NUDT6-SPATA5-SPRY1 locus at human chromosome 4q27-q28.1 were paralogous regions within the human genome. Chimpanzee SPRY4 gene was identified within NW_107083.1 genome sequence. Human, chimpanzee, rat and mouse SPRY4 orthologs, consisting of three exons, were well conserved. SPRY4 gene was identified as the evolutionarily conserved target of WNT/beta-catenin signaling pathway based on the conservation of double TCF/LEF-binding sites within 5'-promoter region of mammalian SPRY4 orthologs. Human SPRY4 mRNA was expressed in embryonic stem (ES) cells, brain, pancreatic islet, colon cancer, head and neck tumor, melanoma, and pancreatic cancer. WNT signaling activation in progenitor cells leads to the growth regulation of progenitor cells themselves through SPRY4 induction, and also to the growth stimulation of proliferating cells through FGF secretion. Epigenetic silencing and loss-of-function mutations of SPRY4 gene in progenitor cells could lead to carcinogenesis. SPRY4 is the pharmacogenomics target in the fields of oncology and regenerative medicine.
Int J Mol Med 2006 Mar
PMID:FGF signaling inhibitor, SPRY4, is evolutionarily conserved target of WNT signaling pathway in progenitor cells. 1646 3


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