Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/beta-catenin signaling.
The Wnt/beta-catenin signaling pathway regulates many developmental processes by modulating gene expression. Wnt signaling induces the stabilization of cytosolic beta-catenin, which then associates with lymphoid enhancer factor and T-cell factor (LEF-1/TCF) to form a transcription complex that activates Wnt target genes. Previously, we have shown that a specific mitogen-activated protein ... (MAP) kinase pathway involving the MAP kinase kinase kinase TAK1 and MAP kinase-related Nemo-like kinase (NLK) suppresses Wnt signaling. In this study, we investigated the relationships among NLK, beta-catenin, and LEF-1/TCF. We found that NLK interacts directly with LEF-1/TCF and indirectly with beta-catenin via LEF-1/TCF to form a complex. NLK phosphorylates LEF-1/TCF on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced LEF-1 transcriptional activity and rendered it resistant to inhibition by NLK. Phosphorylation of TCF-4 by NLK inhibited DNA binding by the beta-catenin-TCF-4 complex. However, this inhibition was abrogated when a mutant form of TCF-4 was used in which both threonines were replaced with valines. These results suggest that NLK phosphorylation on these sites contributes to the down-regulation of LEF-1/TCF transcriptional activity.
Mesh Terms:
Amino Acid Sequence, Amino Acid Substitution, Cells, Cultured, Cytoskeletal Proteins, DNA-Binding Proteins, Down-Regulation, Humans, Intracellular Signaling Peptides and Proteins, Lymphoid Enhancer-Binding Factor 1, MAP Kinase Kinase Kinases, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Mutation, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Sequence Homology, Amino Acid, Serine, Signal Transduction, TCF Transcription Factors, Threonine, Trans-Activators, Transcription Factors, Two-Hybrid System Techniques, Valine, Wnt Proteins, Zebrafish Proteins, beta Catenin
Amino Acid Sequence, Amino Acid Substitution, Cells, Cultured, Cytoskeletal Proteins, DNA-Binding Proteins, Down-Regulation, Humans, Intracellular Signaling Peptides and Proteins, Lymphoid Enhancer-Binding Factor 1, MAP Kinase Kinase Kinases, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Mutation, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Sequence Homology, Amino Acid, Serine, Signal Transduction, TCF Transcription Factors, Threonine, Trans-Activators, Transcription Factors, Two-Hybrid System Techniques, Valine, Wnt Proteins, Zebrafish Proteins, beta Catenin
Mol. Cell. Biol.
Date: Feb. 01, 2003
PubMed ID: 12556497
View in: Pubmed Google Scholar
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