Abstract
Wnt signaling controls a variety of developmental processes. The canonical Wnt/beta-catenin pathway functions to stabilize beta-catenin, and the noncanonical Wnt/Ca(2+) pathway activates Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). In addition, the Wnt/Ca(2+) pathway activated by Wnt-5a antagonizes the Wnt/beta-catenin pathway via an unknown mechanism. The mitogen-activated protein kinase (MAPK) pathway composed of TAK1 MAPK kinase kinase and NLK MAPK also negatively regulates the canonical Wnt/beta-catenin signaling pathway. Here we show that activation of CaMKII induces stimulation of the TAK1-NLK pathway. Overexpression of Wnt-5a in HEK293 cells activates NLK through TAK1. Furthermore, by using a chimeric receptor (beta(2)AR-Rfz-2) containing the ligand-binding and transmembrane segments from the beta(2)-adrenergic receptor (beta(2)AR) and the cytoplasmic domains from rat Frizzled-2 (Rfz-2), stimulation with the beta-adrenergic agonist isoproterenol activates activities of endogenous CaMKII, TAK1, and NLK and inhibits beta-catenin-induced transcriptional activation. These results suggest that the TAK1-NLK MAPK cascade is activated by the noncanonical Wnt-5a/Ca(2+) pathway and antagonizes canonical Wnt/beta-catenin signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic beta-Agonists / pharmacology
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Animals
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Calcium / metabolism*
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cells, Cultured
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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Frizzled Receptors
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Humans
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Intracellular Signaling Peptides and Proteins
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Isoproterenol / pharmacology
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism*
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Rats
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Receptors, Adrenergic, beta-2 / drug effects
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Receptors, Adrenergic, beta-2 / genetics
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Receptors, Adrenergic, beta-2 / metabolism
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Receptors, G-Protein-Coupled
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Receptors, Neurotransmitter / genetics
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Receptors, Neurotransmitter / metabolism
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Recombinant Proteins / drug effects
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Signal Transduction
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Wnt Proteins
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Wnt-5a Protein
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beta Catenin
Substances
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Adrenergic beta-Agonists
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CTNNB1 protein, human
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Ctnnb1 protein, rat
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Cytoskeletal Proteins
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FZD2 protein, human
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Frizzled Receptors
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Fzd2 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins
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Receptors, Adrenergic, beta-2
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Receptors, G-Protein-Coupled
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Receptors, Neurotransmitter
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Recombinant Proteins
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Trans-Activators
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WNT5A protein, human
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Wnt Proteins
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Wnt-5a Protein
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beta Catenin
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Fzd2 protein, rat
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NLK protein, human
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Nlk protein, mouse
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Isoproterenol
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Calcium