title: The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling.
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.
authors.affiliation: Department of Molecular Biology, Graduate School of Science, Nagoya University, Chikusa-ku, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Ishitani
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kishida
authors.forename: Junko
authors.initials: J
authors.lastname: Hyodo-Miura
authors.forename: Naoto
authors.initials: N
authors.lastname: Ueno
authors.forename: Jun
authors.initials: J
authors.lastname: Yasuda
authors.forename: Marian
authors.initials: M
authors.lastname: Waterman
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shibuya
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.forename: Jun
authors.initials: J
authors.lastname: Ninomiya-Tsuji
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D051157:Frizzled Receptors; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000318:Adrenergic beta-Agonists; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003598:Cytoskeletal Proteins; D051157:Frizzled Receptors; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter; D011994:Recombinant Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D000099151:MAP Kinase Kinase Kinase 7; C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; C489742:FZD2 protein, human; C489743:Fzd2 protein, mouse; C085389:WNT5A protein, human; C078604:Fzd2 protein, rat; C470551:NLK protein, human; C408347:Nlk protein, mouse