The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF.
The Wnt signalling pathway regulates many developmental processes through a complex of beta-catenin and the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of high-mobility-group transcription factors. Wnt stabilizes cytosolic beta-catenin, which then binds to TCF and activates gene transcription. This signalling cascade is conserved in vertebrates, Drosophila and Caenorhabditis elegans. In C. elegans, the proteins MOM-4 and LIT-1 regulate Wnt signalling to polarize responding cells during embryogenesis. MOM-4 and LIT-1 are homologous to TAK1 (a kinase activated by transforming growth factor-beta) mitogen-activated protein-kinase-kinase kinase (MAP3K) and MAP kinase (MAPK)-related NEMO-like kinase (NLK), respectively, in mammalian cells. These results raise the possibility that TAK1 and NLK are also involved in Wnt signalling in mammalian cells. Here we show that TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. Injection of NLK suppresses the induction of axis duplication by microinjected beta-catenin in Xenopus embryos. NLK phosphorylates TCF/LEF factors and inhibits the interaction of the beta-catenin-TCF complex with DNA. Thus, the TAK1-NLK-MAPK-like pathway negatively regulates the Wnt signalling pathway.
Ishitani
T
T
Department of Molecular Biology, Graduate School of Science, Nagoya University, Japan.
Ninomiya-Tsuji
J
J
Nagai
S
S
Nishita
M
M
Meneghini
M
M
Barker
N
N
Waterman
M
M
Bowerman
B
B
Clevers
H
H
Shibuya
H
H
Matsumoto
K
K
D000818:Animals; D019556:COS Cells; D017173:Caenorhabditis elegans; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D010766:Phosphorylation; D017354:Point Mutation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014981:Xenopus; D029867:Xenopus Proteins; D051176:beta Catenin; D000099151:MAP Kinase Kinase Kinase 7
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003598:Cytoskeletal Proteins; D004247:DNA; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D029867:Xenopus Proteins; D051176:beta Catenin; D000099151:MAP Kinase Kinase Kinase 7; C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; C544894:TCF7L2 protein, human; C544896:tcf7l2 protein, Xenopus; C470551:NLK protein, human