Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues.
Combining with an extracellular signal and transmitting the signal across the membrane by activating an associated G-protein; promotes the exchange of GDP for GTP on the alpha subunit of a heterotrimeric G-protein complex.
Members of the Wnt family of lipoglycoproteins initiate signaling by binding to Frizzled (Fz) receptors, and the signal is then relayed by Disheveled (Dvl). The Dvl PDZ domain is known to interact directly with a peptide derived from the KTXXXW motif of Fz7, which is conserved in all known Fz subtypes. We found that an extended region spanning the KTXXXW motif on both its N-terminal and C-terminal sides dramatically influences the affinity of peptides derived from Fz7 for Dvl PDZ. An alanine scanning study identified the specific residues external to the KTXXXW motif that are important for high-affinity binding. In a circular dichroism analysis, mutation of some of these critical residues resulted in peptide conformational changes, suggesting that the secondary structure of the peptides contributes to Fz-Dvl PDZ binding. Of the 10 known Fz subtypes, peptides derived from only Fz1, Fz2, Fz3, Fz4, and Fz7 directly bound to Dvl PDZ domain in our study. Other Fz subtypes, including some known to be involved in Wnt/beta-catenin signaling (Fz5, Fz9), did not bind to Dvl, suggesting that direct interaction with Dvl PDZ does not determine the subtype-specific functionality of Fz. Molecular modeling and circular dichroism studies indicated that the Fz peptides that bind to Dvl PDZ domain form specific conformations that are different from those of nonbinding peptides.
The process whose specific outcome is the progression of the brain over time, from its formation to the mature structure. Brain development begins with patterning events in the neural tube and ends with the mature structure that is the center of thought and emotion. The brain is responsible for the coordination and control of bodily activities and the interpretation of information from the senses (sight, hearing, smell, etc.).
The series of molecular signals initiated by binding of a Wnt protein to a frizzled family receptor on the surface of the target cell, followed by propagation of the signal via beta-catenin, and ending with a change in transcription of target genes. In this pathway, the activated receptor signals via downstream effectors that result in the inhibition of beta-catenin phosphorylation, thereby preventing degradation of beta-catenin. Stabilized beta-catenin can then accumulate and travel to the nucleus to trigger changes in transcription of target genes.
Signal transduction via the Frizzled family of seven-transmembrane receptors controls important developmental processes. Aberrant signaling caused by altered Frizzled receptor activity or by mutations in downstream signaling components has been implicated in several adult pathologies. A diverse array of intracellular signaling pathways has been suggested to transduce the signals exerted in cells when secreted ligands of the Wnt family bind to Frizzled receptors. Studies with a chimeric receptor composed of Frizzled-2 and the beta2-adrenergic receptor have suggested that the binding of Wnt-5a to Frizzled-2 results in the activation of G proteins of the Galpha(i) family, the mobilization of calcium from intracellular stores and the induction of gene transcription through nuclear factor of activated T cells. In this report, we demonstrate by using beta-lactamase reporter gene technology that full-length, wild-type human Frizzled-2 does not couple to calcium-mediated signaling in HEK293 cells following stimulation with purified recombinant mouse Wnt-5a. In contrast, when stimulated with recombinant mouse Wnt-3a, Frizzled-2 activates the canonical Wnt/Frizzled signaling pathway, involving the transcriptional modulator beta-catenin. Our report underlines the importance of using cell lines stably overexpressing wild-type Frizzled receptors and the use of purified ligands when studying receptor pharmacology. This approach has allowed us to measure the half-maximal concentration for activation of human Frizzled-2 (1.5+/-0.4 nM; avg.+/-SD) and human Frizzled-1 (1.3+/-0.5 nM) following stimulation by Wnt-3a. Our results suggest that there is receptor redundancy with regard to Wnt-3a reception. In addition, we introduce beta-lactamase reporter gene technology as an alternative to luciferase-based reporters to measure Frizzled receptor modulation for the discovery of Frizzled receptor-interacting drugs.
Although Wnt-Frizzled (Fzd) signaling is critical in the pathophysiology of carcinomas, its role in human breast cancer has been difficult to establish. We show here that the adaptor protein Na(+)/H(+) exchange regulatory factor1 (NHERF1), a protein abundantly expressed in normal mammary epithelium, regulates Wnt signaling, maintaining low levels of β-catenin activation. NHERF1's effects are mediated by direct interactions between one of its PSD-95/drosophila discs large/ZO-1 (PDZ) domains and the C-terminus of a subset of Fzd receptors. Loss of NHERF1 in breast cancer cell lines enhances canonical Wnt signaling and Wnt-dependent cell proliferation. Furthermore, the mammary glands of NHERF1-knockout mice exhibit increased mammary duct density accompanied by increased proliferation and β-catenin activity. Finally, we demonstrate a negative correlation between NHERF1 expression and nuclear β-catenin in human breast carcinomas. Taken together, these results provide a novel insight into the regulation of Wnt signaling in normal and neoplastic breast tissues, and identify NHERF1 as an important regulator of the pathogenesis of breast tumors.
BACKGROUND: Wnt signaling is mediated through 1) the beta-catenin dependent canonical pathway and, 2) the beta-catenin independent pathways. Multiple receptors, including Fzds, Lrps, Ror2 and Ryk, are involved in Wnt signaling. Ror2 is a single-span transmembrane receptor-tyrosine kinase (RTK). The functions of Ror2 in mediating the non-canonical Wnt signaling have been well established. The role of Ror2 in canonical Wnt signaling is not fully understood. RESULTS: Here we report that Ror2 also positively modulates Wnt3a-activated canonical signaling in a lung carcinoma, H441 cell line. This activity of Ror2 is dependent on cooperative interactions with Fzd2 but not Fzd7. In addition, Ror2-mediated enhancement of canonical signaling requires the extracellular CRD, but not the intracellular PRD domain of Ror2. We further provide evidence that the positive effect of Ror2 on canonical Wnt signaling is inhibited by Dkk1 and Krm1 suggesting that Ror2 enhances an Lrp-dependent STF response. CONCLUSION: The current study demonstrates the function of Ror2 in modulating canonical Wnt signaling. These findings support a functional scheme whereby regulation of Wnt signaling is achieved by cooperative functions of multiple mediators.
The process whose specific outcome is the progression of an embryo from its formation until the end of its embryonic life stage. The end of the embryonic stage is organism-specific. For example, for mammals, the process would begin with zygote formation and end with birth. For insects, the process would begin at zygote formation and end with larval hatching. For plant zygotic embryos, this would be from zygote formation to the end of seed dormancy. For plant vegetative embryos, this would be from the initial determination of the cell or group of cells to form an embryo until the point when the embryo becomes independent of the parent plant.
The process in which a relatively unspecialized cell acquires specialized features of an epithelial cell, any of the cells making up an epithelium.
IBARefGenome
G-protein coupled receptor signaling pathway coupled to cGMP nucleotide second messengerdefinition[GO:0007199]‹silver
The series of molecular signals generated as a consequence of a G-protein coupled receptor binding to its physiological ligand, followed by activation of guanylyl cyclase (GC) activity and a subsequent increase in the concentration of cyclic GMP (cGMP).
The process whose specific outcome is the progression of the gonad over time, from its formation to the mature structure. The gonad is an animal organ that produces gametes; in some species it also produces hormones.
The biological process whose specific outcome is the progression of the hard palate from an initial condition to its mature state. This process begins with the formation of the structure and ends with the mature structure, whatever form that may be including its natural destruction. The hard palate is the anterior portion of the palate consisting of bone and mucous membranes.
The process whose specific outcome is the progression of an inner ear receptor cell over time, from its formation to the mature structure. Cell development does not include the steps involved in committing a cell to a specific fate.
The process in which the anatomical structures of the outflow tract are generated and organized. The outflow tract is the portion of the heart through which blood flows into the arteries.
IEAOrtholog Compara
Planar cell polarity pathway involved in neural tube closuredefinition[GO:0090179]‹silver
The series of molecular signals initiated by binding of a Wnt protein to a receptor on the surface of the target cell where activated receptors signal via downstream effectors that modulates the establishment of planar polarity contributing to neural tube closure.
Malignant melanoma is one of the most aggressive human neoplasms which develop from the malignant transformation of normal epithelial melanocytes and share the lineage with retinal cells. cGMP-phosphodiesterase 6 (PDE6) is one of the cancer-retina antigens newly identified in melanoma cells. Normally, PDE6 hydrolyzes the photoreceptor second messenger cGMP allowing the visual signal transduction in photoreceptor cells. cGMP also play an important signaling role in stimulating melanogenesis in human melanocytes. Here, we present evidence that PDE6 is a key enzyme regulating the cGMP metabolism in melanoma cells. Decrease in intracellular cGMP leads to calcium accumulation in melanoma cells. In these cells, cGMP-phosphodiesterase 6 can be activated by another cancer-retina antigen, transducin, through Wnt5a-Frizzled-2 cascade, which leads to a lowering of cGMP and an increase in intracellular calcium mobilization. Thus, the aberrant expression of PDE6 may control cGMP metabolism and calcium homeostasis in melanoma cells.
Positive regulation of sequence-specific DNA binding transcription factor activitydefinition[GO:0051091]
Any process that activates or increases the frequency, rate or extent of activity of a transcription factor, any factor involved in the initiation or regulation of transcription.
Signal transduction via the Frizzled family of seven-transmembrane receptors controls important developmental processes. Aberrant signaling caused by altered Frizzled receptor activity or by mutations in downstream signaling components has been implicated in several adult pathologies. A diverse array of intracellular signaling pathways has been suggested to transduce the signals exerted in cells when secreted ligands of the Wnt family bind to Frizzled receptors. Studies with a chimeric receptor composed of Frizzled-2 and the beta2-adrenergic receptor have suggested that the binding of Wnt-5a to Frizzled-2 results in the activation of G proteins of the Galpha(i) family, the mobilization of calcium from intracellular stores and the induction of gene transcription through nuclear factor of activated T cells. In this report, we demonstrate by using beta-lactamase reporter gene technology that full-length, wild-type human Frizzled-2 does not couple to calcium-mediated signaling in HEK293 cells following stimulation with purified recombinant mouse Wnt-5a. In contrast, when stimulated with recombinant mouse Wnt-3a, Frizzled-2 activates the canonical Wnt/Frizzled signaling pathway, involving the transcriptional modulator beta-catenin. Our report underlines the importance of using cell lines stably overexpressing wild-type Frizzled receptors and the use of purified ligands when studying receptor pharmacology. This approach has allowed us to measure the half-maximal concentration for activation of human Frizzled-2 (1.5+/-0.4 nM; avg.+/-SD) and human Frizzled-1 (1.3+/-0.5 nM) following stimulation by Wnt-3a. Our results suggest that there is receptor redundancy with regard to Wnt-3a reception. In addition, we introduce beta-lactamase reporter gene technology as an alternative to luciferase-based reporters to measure Frizzled receptor modulation for the discovery of Frizzled receptor-interacting drugs.
BACKGROUND: Wnt signaling is mediated through 1) the beta-catenin dependent canonical pathway and, 2) the beta-catenin independent pathways. Multiple receptors, including Fzds, Lrps, Ror2 and Ryk, are involved in Wnt signaling. Ror2 is a single-span transmembrane receptor-tyrosine kinase (RTK). The functions of Ror2 in mediating the non-canonical Wnt signaling have been well established. The role of Ror2 in canonical Wnt signaling is not fully understood. RESULTS: Here we report that Ror2 also positively modulates Wnt3a-activated canonical signaling in a lung carcinoma, H441 cell line. This activity of Ror2 is dependent on cooperative interactions with Fzd2 but not Fzd7. In addition, Ror2-mediated enhancement of canonical signaling requires the extracellular CRD, but not the intracellular PRD domain of Ror2. We further provide evidence that the positive effect of Ror2 on canonical Wnt signaling is inhibited by Dkk1 and Krm1 suggesting that Ror2 enhances an Lrp-dependent STF response. CONCLUSION: The current study demonstrates the function of Ror2 in modulating canonical Wnt signaling. These findings support a functional scheme whereby regulation of Wnt signaling is achieved by cooperative functions of multiple mediators.
Signal transduction via the Frizzled family of seven-transmembrane receptors controls important developmental processes. Aberrant signaling caused by altered Frizzled receptor activity or by mutations in downstream signaling components has been implicated in several adult pathologies. A diverse array of intracellular signaling pathways has been suggested to transduce the signals exerted in cells when secreted ligands of the Wnt family bind to Frizzled receptors. Studies with a chimeric receptor composed of Frizzled-2 and the beta2-adrenergic receptor have suggested that the binding of Wnt-5a to Frizzled-2 results in the activation of G proteins of the Galpha(i) family, the mobilization of calcium from intracellular stores and the induction of gene transcription through nuclear factor of activated T cells. In this report, we demonstrate by using beta-lactamase reporter gene technology that full-length, wild-type human Frizzled-2 does not couple to calcium-mediated signaling in HEK293 cells following stimulation with purified recombinant mouse Wnt-5a. In contrast, when stimulated with recombinant mouse Wnt-3a, Frizzled-2 activates the canonical Wnt/Frizzled signaling pathway, involving the transcriptional modulator beta-catenin. Our report underlines the importance of using cell lines stably overexpressing wild-type Frizzled receptors and the use of purified ligands when studying receptor pharmacology. This approach has allowed us to measure the half-maximal concentration for activation of human Frizzled-2 (1.5+/-0.4 nM; avg.+/-SD) and human Frizzled-1 (1.3+/-0.5 nM) following stimulation by Wnt-3a. Our results suggest that there is receptor redundancy with regard to Wnt-3a reception. In addition, we introduce beta-lactamase reporter gene technology as an alternative to luciferase-based reporters to measure Frizzled receptor modulation for the discovery of Frizzled receptor-interacting drugs.
The series of events required for an organism to receive an olfactory stimulus, convert it to a molecular signal, and recognize and characterize the signal. Olfaction involves the detection of chemical composition of an organism's ambient medium by chemoreceptors. This is a neurological process.
The process whose specific outcome is the progression of the vasculature over time, from its formation to the mature structure. The vasculature is an interconnected tubular multi-tissue structure that contains fluid that is actively transported around the organism.
The series of molecular signals initiated by binding of a Wnt protein to a receptor on the surface of the target cell where activated receptors leads to an increase in intracellular calcium and activation of protein kinase C (PKC).
IBARefGenome
Pathways
According to KEGG, this protein belongs to the following pathways:
Protein involved in the Wnt signaling pathway. Wnts are a large family of cysteine-rich secreted glycoproteins that control development in organisms ranging from nematodes to mammals. Wnt genes are defined by sequence homology to the original members of the family, Wnt1 in the mouse and wingless (wg) in Drosophila. Wnt signaling is a very complex pathway which includes numerous ligands, receptors and transcriptional effectors. There is a well-characterized canonical pathway as well as diverse, less-characterized noncanonical pathways. Several components of Wnt signaling are implicated in the genesis of human cancer.
Protein involved in development, the process whereby a multicellular organism develops from its early immature forms, e.g., zygote, larva, embryo, into an adult.
Receptors which transduce extracellular signals across the cell membrane. At the external side they receive a ligand (a photon in case of opsins), and at the cytosolic side they activate a guanine nucleotide-binding (G) protein. These receptors are hydrophobic proteins that cross the membrane seven times.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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