The TAK1–NLK–MAPK-related pathway antagonizes signalling between β-catenin and transcription factor TCF

Abstract

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.

TAK1 represses transcription of the human telomerase reverse transcriptase gene

“…Although our results showed that TAK1 represses the hTERT promoter activity in an E-box-independent manner, we cannot exclude the possibility that TAK1 represses the hTERT promoter even in an E-box-dependent manner. In fact, a b-catenin/Tcf-4 complex augments c-Myc gene transcription by binding to the Tcf-4-binding sites in the c-Myc promoter (He et al, 1998); however, this binding is impaired by the MAPK-related NEMO-like kinase (NLK) pathway activated by TAK1 (Ishitani et al, 1999). Thus, in the future, we must investigate whether TAK1 represses c-Myc expression by activating the NLK pathway and consequently antagonizing the b-catenin/Tcf-4 complex and whether this c-Myc repression results in hTERT promoter repression in an E-box-dependent manner.…”

When pathways collide: collaboration and connivance among signalling proteins in development

“…Early studies showed that overexpressed Wnt5a can block the stabilization of β-catenin induced by Wnt-1 39 . Expression of Wnt5a can also activate a nemo-like kinase (NLK) that phosphorylates TCF transcription factors, thus inhibiting canonical Wnt signaling 40,41 . In fact, it appears that simply inhibiting canonical signaling can, in some conditions, lead to PCP effects.…”

Wnt signaling and skeletal development

“…Another β-catenin binding protein, ICAT, can block the binding of β-catenin to TCF [21] and also can lead to the dissociation of complexes between β-catenin, LEF, and CBP/p300 [22,23]. TCF can be phosphorylated by the mitogen-activated protein (MAP) kinase-related protein kinase NLK/Nemo [24]. The phosphorylation of TCF/LEF by activated Nemo is thought to diminish the DNA-binding affinity of the β-catenin/TCF/LEF complex, thereby affecting transcriptional regulation of Wnt target genes [24,25].…”

“…TCF can be phosphorylated by the mitogen-activated protein (MAP) kinase-related protein kinase NLK/Nemo [24]. The phosphorylation of TCF/LEF by activated Nemo is thought to diminish the DNA-binding affinity of the β-catenin/TCF/LEF complex, thereby affecting transcriptional regulation of Wnt target genes [24,25].…”