MAP kinase and Wnt pathways converge to downregulate an HMG-domain repressor in Caenorhabditis elegans
Abstract
The signalling protein Wnt regulates transcription factors containing high-mobility-group (HMG) domains to direct decisions on cell fate during animal development. In Caenorhabditis elegans, the HMG-domain-containing repressor POP-1 distinguishes the fates of anterior daughter cells from their posterior sisters throughout development, and Wnt signalling downregulates POP-1 activity in one posterior daughter cell called E. Here we show that the genes mom-4 and lit-1 are also required to downregulate POP-1, not only in E but also in other posterior daughter cells. Consistent with action in a common pathway, mom-4 and lit-1 exhibit similar mutant phenotypes and encode components of the mitogen-activated protein kinase (MAPK) pathway that are homologous to vertebrate transforming-growth-factor-beta-activated kinase (TAK1) and NEMO-like kinase (NLK), respectively. Furthermore, MOM-4 and TAK1 bind related proteins that promote their kinase activities. We conclude that a MAPK-related pathway cooperates with Wnt signal transduction to downregulate POP-1 activity. These functions are likely to be conserved in vertebrates, as TAK1 and NLK can downregulate HMG-domain-containing proteins related to POP-1.
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A MAPK-related pathway acts in concert with Wnt signaling to establish anterior-posterior polarity in C. elegans.
“Thus, a MAPK-related pathway acts in concert with Wnt signaling to establish anterior-posterior polarity in C. elegans.”
In C. elegans, WRM-1 down-regulates, rather than activates, POP-1.
“whereas in C. elegans, WRM-1 down-regulates, rather than activates, POP-1 (16, 21, 22, 30).”
The mom-4 gene encodes a MAPK kinase kinase-like protein related to the mammalian protein kinase TAK1.
“The mom-4 gene encodes a MAPK kinase kinase-like protein related to the mammalian protein kinase TAK1.”
The lit-1 gene encodes a MAPK-like protein similar to the Drosophila Nemo protein kinase and the mouse Nemo-like kinase (NLK).
“The lit-1 gene encodes a mitogen-activated protein kinase (MAPK)-like protein similar to the Drosophila Nemo protein kinase and the mouse Nemo-like kinase (NLK).”
Mutations in lit-1 or mom-4 cause a loss of polarity and POP-1 asymmetry.
“Mutations in lit-1 or mom-4 cause a loss of polarity and POP-1 asymmetry (16, 22, 27).”
POP-1, a LEF-1/TCF-related protein, functions to repress gene expression.
“POP-1, a LEF-1/TCF-related protein, functions to repress gene expression, and Wnt signaling down-regulates the activity of POP-1 (15, 16, 21, 22, 30).”
Wnt signaling down-regulates the activity of POP-1.
“POP-1, a LEF-1/TCF-related protein, functions to repress gene expression, and Wnt signaling down-regulates the activity of POP-1 (15, 16, 21, 22, 30).”
NLK proteins function as important regulators of cell growth, patterning, and death by controlling diverse signaling pathways including Wnt and Notch pathways.
“Across species, NLK proteins function as important regulators of cell growth, patterning, and death by controlling diverse signaling pathways including Wnt and Notch pathways (Ishitani et al., 1999; Meneghini et al., 1999; Rocheleau et al., 1999; Verheyen et al., 2001; Rottinger et al., 2006).”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Meneghini et al., 1999
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References 29 · Cited by 293
- Authors
- Meneghini, M. D., Ishitani, T., Carter, J. C., Hisamoto, N., Ninomiya-Tsuji, J., Thorpe, C. J., Hamill, D. R., Matsumoto, K., & Bowerman, B.
- Affiliations
- University of Oregon (US)
- Nagoya University (JP)
- Corresponding author
- Bowerman, Bruce
- ORCID
- Venue
- Nature
- Published
- 1999-06
- Volume
- 399
- Issue
- 6738
- Pages
- 793-797
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1640296793
- Cited by
- 293
- References
- 29
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 6 · 2016: 5 · 2015: 6 · 2014: 13 · 2013: 13 · 2012: 11
- FWCI
- 9.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Public Health Service
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Wnt signaling, MAPK signaling, POP-1, Caenorhabditis elegans, TAK1, Nemo-like kinase, cell fate specification, transcriptional repression
- MeSH terms
- MAP Kinase Kinase Kinase 7, Amino Acid Sequence, Animals, Carrier Proteins, Cell Line, Cloning, Molecular, DNA-Binding Proteins, Enzyme Activation, High Mobility Group Proteins, Humans, Membrane Proteins, Molecular Sequence Data, Protein Kinases, Proto-Oncogene Proteins, Signal Transduction, Down-Regulation, Caenorhabditis elegans, Genes, Helminth, Protein Serine-Threonine Kinases, Sequence Homology, Amino Acid, Calcium-Calmodulin-Dependent Protein Kinases, Gene Expression Regulation, Developmental, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Kinase Kinases, Potassium Channels, Voltage-Gated, Caenorhabditis elegans Proteins, Zebrafish Proteins, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Adaptor Proteins, Signal Transducing, Wnt Proteins
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