The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling.
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.
Ishitani
Tohru
T
Department of Molecular Biology, Graduate School of Science, Nagoya University, Chikusa-ku, Japan.
Kishida
Satoshi
S
Hyodo-Miura
Junko
J
Ueno
Naoto
N
Yasuda
Jun
J
Waterman
Marian
M
Shibuya
Hiroshi
H
Moon
Randall T
RT
Ninomiya-Tsuji
Jun
J
Matsumoto
Kunihiro
K
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
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