The DOI matches its Crossref record; 37 of the 38 references it cites were found in a registry or an index; 6 of the 89 sources its claims cite were checked for support.
Regulation of Lymphoid Enhancer Factor 1/T-Cell Factor by Mitogen-Activated Protein Kinase-Related Nemo-Like Kinase-Dependent Phosphorylation in Wnt/β-Catenin Signaling
Open accessAbstract
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.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
NLK directly binds LEF-1/TCF and phosphorylates conserved central serine/threonine residues, thereby inhibiting β-catenin–TCF DNA binding and LEF-1/TCF transcriptional activity. β-Catenin associates with NLK indirectly through LEF-1/TCF, and β-catenin enhances NLK phosphorylation of TCF-4.
Key findings
- NLK interacted directly with LEF-1/TCF but not appreciably with β-catenin; LEF-1/TCF bridged β-catenin to NLK, and β-catenin enhanced NLK phosphorylation of TCF-4 in vitro.
- NLK phosphorylated LEF-1 at Thr-155 and Ser-166 and TCF-4 at Thr-178 and Thr-189; LEF-1(2A) and TCF-4(2V) mutants showed greatly reduced NLK phosphorylation.
- LEF-1(2A) enhanced Wnt-1-induced TOPFLASH reporter activity more strongly than wild-type LEF-1 and was resistant to NLK inhibition; Wnt-1 alone induced the reporter about fourfold.
- NLK phosphorylation of TCF-4 inhibited DNA binding by the β-catenin–TCF-4 complex, while TCF-4(2V) enhanced DNA binding and remained bound even with NLK expression.
Methods
- Biochemical and cell-based study using human embryonic kidney 293 and HeLa cells, with transfected Flag-NLK, T7/HA-LEF-1, TCF-4, β-catenin, and mutant constructs.
- Assays included yeast two-hybrid, coimmunoprecipitation/immunoblotting, in vitro kinase assays with [γ-32P]ATP, TOPFLASH/FOPFLASH luciferase reporter assays, and gel mobility shift assays.
- Main analysis compared wild-type versus phosphorylation-site mutants LEF-1(2A) and TCF-4(2V) for NLK binding, phosphorylation, β-catenin association, transcriptional activity, and DNA binding.
Limitations
- Stated in the paper: weak residual phosphorylation of LEF-1(2A) and TCF-4(2V) suggests additional NLK phosphorylation sites may exist; NLK overexpression failed to suppress endogenous LEF-1/TCF-dependent transcription in HeLa cells, suggesting a resistant complex.
- Evident from the text: mechanistic conclusions rely heavily on overexpression in 293/HeLa cell lines and in vitro kinase/gel-shift assays, with no vertebrate in vivo requirement for these phosphorylation sites tested here.
- Evident from the text: the mechanism by which NLK phosphorylation distal to the DNA-binding domain inhibits β-catenin–TCF-4 DNA binding was not determined.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
6 of 89 cited sources checked · 3 supported · 1 flagged · accuracy not yet measured
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Indeed, WRM-1, which is only 19% identical to vertebrate β-catenin, does not bind to the POP-1 β-catenin-binding domain per se but weakly binds full-length POP-1 (14, 19, 22).”
What the sources say
- Not checked — no full text of the sourcecites [14] source
- Disputedcites [19] sourceExperimental — accuracy not yet measured
The percentage-identity table in the section on β-catenin family members across species (page unavailable) gives 17% identity between WRM-1 and human β-catenin, not 19%. The Methods section says these percentages were calculated from sequence alignments. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
- Not checked — no full text of the sourcecites [22] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe cited sources support only part of this claim — read each source’s verdict below.
In the paper
“HeLa cells, which contain low levels of endogenous LEF-1/TCF (10).”
What the sources say
- Partly supportedcites [10] sourceExperimental — accuracy not yet measured
The Results (page not provided) describe HeLa cells as not expressing LEF-1, supporting low endogenous LEF-1 relative to LEF-1-expressing Jurkat cells. The passage does not establish the level of endogenous TCF in HeLa cells. (LLM, conf=0.82)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Indeed, WRM-1, which is only 19% identical to vertebrate β-catenin, does not bind to the POP-1 β-catenin-binding domain per se but weakly binds full-length POP-1 (14, 19, 22).”
What the sources say
- Not checked — no full text of the sourcecites [14] source
- Partly supportedcites [19] sourceExperimental — accuracy not yet measured
In the protein-interaction results (page unavailable), WRM-1 interacts weakly with POP-1 even after deletion of POP-1’s amino-terminal β-catenin-binding region. This supports an interaction that does not require that region, but the paper does not test whether WRM-1 can bind the region itself; it presents a different mode of interaction as a suggestion, not a categorical finding. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [22] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Indeed, WRM-1, which is only 19% identical to vertebrate β-catenin, does not bind to the POP-1 β-catenin-binding domain per se but weakly binds full-length POP-1 (14, 19, 22).”
What the sources say
- Not checked — no full text of the sourcecites [14] source
- Supportedcites [19] source
In the β-catenin family members across species section, the POP-1 interaction table records a weak WRM-1 interaction with full-length POP-1; the accompanying text explicitly calls it a weak interaction. The finding comes from a yeast interaction assay, so “binds” is a paraphrase of that result. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [22] source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NLK phosphorylates LEF-1/TCF on two serine/threonine residues located in its central region.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mutation of both residues to alanine enhanced LEF-1 transcriptional activity and rendered it resistant to inhibition by NLK.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mutation of both residues to alanine enhanced LEF-1 transcriptional activity and rendered it resistant to inhibition by NLK.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that NLK interacts directly with LEF-1/TCF and indirectly with β-catenin via LEF-1/TCF to form a complex.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that NLK interacts directly with LEF-1/TCF and indirectly with β-catenin via LEF-1/TCF to form a complex.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Phosphorylation of TCF-4 by NLK inhibited DNA binding by the β-catenin-TCF-4 complex.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- Probably not a substantial claim. 17
- It may state two separate claims as one. 17
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“β-Catenin then translocates into the nucleus, where it forms a complex with the HMG box class of transcription factors, including lymphoid enhancer factor 1 (LEF-1) and T-cell factor (TCF), and activates the transcription of its target genes (5, 17, 20).”
What the sources say
- Supportedcites [5] source
The “Binding of Arm/β-catenin to Tcf-LEF-1” section (page not specified) says β-catenin accumulates in the nucleus after Wnt stimulation, binds HMG-box factors of the Tcf-LEF-1 family, and forms complexes that activate transcription. This supports the cited paraphrase. (LLM, conf=0.93)
- Supportedcites [17] source
The section on nuclear β-catenin says LEF-1 and XTcf-3, both HMG-box factors, bind β-catenin and translocate it to the nucleus. The Figure 3 discussion says the resulting complex binds DNA and alters transcription; the paper also reports transactivation of a reporter gene. Page numbers are not supplied in our copy. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [20] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
- Supported
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“These results suggest that Wnt signaling and the MAPK-related cascade both act to control polarity by regulating POP-1 and that integration of two signals occurs at the level of complex formation between WRM-1 and LIT-1.”
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“TAK1 functions upstream of NLK and enhances NLK kinase activity.”
What the sources say
- Not checked — no full text of the sourcecites [13] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Active NLK phosphorylates LEF-1/TCF and prevents the β-catenin-TCF complex from binding to DNA, thereby inhibiting the ability of β-catenin-TCF to activate transcription.”
What the sources say
- Not checked — no full text of the sourcecites [13] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“LIT-1 interacts directly with WRM-1, and this complex can phosphorylate POP-1 in a LIT-1 kinase domain-dependent manner, indicating that these pathways converge at WRM-1 (22).”
What the sources say
- Not checked — no full text of the sourcecites [22] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Consistent with this, ectopic expression of NLK blocks double-axis formation in Xenopus induced by overexpression of β-catenin but not by the downstream components siamois and twin (13).”
What the sources say
- Not checked — no full text of the sourcecites [13] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In this complex, LEF-1/TCF provides the DNA-binding domain while β-catenin contributes the transactivation domain, allowing the activation of LEF-1/TCF target genes.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Although LEF-1/TCF family members share overall sequence similarity, these two regions are particularly conserved (18).”
What the sources say
- Not checked — no full text of the sourcecites [18] source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In C. elegans, WRM-1 and LIT-1 appear to form a stable protein complex in vivo (22).”
What the sources say
- Not checked — no full text of the sourcecites [22] source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In C. elegans, WRM-1 (β-catenin) directly interacts with and activates LIT-1 (NLK).”
What the sources say
- Not checked — no full text of the sourcecites [22] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Active LIT-1 then phosphorylates WRM-1 and POP-1 (LEF-1/TCF) (22).”
What the sources say
- Not checked — no full text of the sourcecites [22] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“S/TP motifs are consensus sites for MAPK phosphorylation (31).”
What the sources say
- Not checked — no full text of the sourcecites [31] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“LEF-1/TCF has been shown to form a complex with β-catenin in response to Wnt stimulation (2, 4, 18, 34).”
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Although LEF-1/TCF family members share overall sequence similarity, these two regions are particularly conserved (18).”
What the sources say
- Not checked — no full text of the sourcecites [18] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, these results do not completely rule out the possibility that these residues play a role in the association of LEF-1 and TCF-4 with NLK.”
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“WRM-1 activates the LIT-1 protein kinase, leading to phosphorylation of WRM-1, LIT-1, and POP-1.”
What the sources say
- Not checked — no full text of the sourcecites [22] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that the LEF-1(2A) and TCF-4(2V) mutations abrogate phosphorylation per se and do not otherwise affect the interaction with NLK in vivo.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The LEF-1 protein contains a COOH-terminal HMG DNA-binding domain and an NH2-terminal β-catenin-binding domain.
In the paper
“Rocheleau et al. (22) have demonstrated that the WRM-1 protein binds to and activates LIT-1.”
What the sources say
- Not checked — no full text of the sourcecites [22] source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“T-cell polarity is controlled by LIN-44 (Wnt), LIN-17 (Frizzled receptor), and POP-1 (7, 8, 9, 26).”
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings indicate that the components of the Wnt pathway in C. elegans and vertebrates are similar but have different activities.”
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The components of the Wnt pathway (β-catenin, LEF-1/TCF, NLK) are conserved in vertebrates.
In the paper
“POP-1 plays a negative role in Wnt signaling and is inhibited by WRM-1 through LIT-1-mediated phosphorylation of POP-1 (22).”
What the sources say
- Not checked — no full text of the sourcecites [22] source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“The β-catenin-LEF-1/TCF complex, in turn, activates Wnt target genes in the nucleus (2, 4, 18, 34).”
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“On the other hand, β-catenins can stably bind to LEF-1/TCF (2).”
What the sources say
- Not checked — no full text of the sourcecites [2] source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is likely that functionally conserved serine and threonine residues are also present between the β-catenin-binding domain and the DNA-binding domain of LEF-1/TCF that regulate its activity.”
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The C. elegans LIT-1 protein interacts directly with WRM-1, and this complex can phosphorylate POP-1 in a manner that requires the LIT-1 kinase domain (22).”
What the sources say
- Not checked — no full text of the sourcecites [22] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“This activation leads to the phosphorylation of POP-1 and apparent changes in its subcellular localization (22).”
What the sources say
- Not checked — no full text of the sourcecites [22] source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“We have previously shown that NLK phosphorylates TCF-4 and prevents the β-catenin-TCF-4 complex from binding DNA (13).”
What the sources say
- Not checked — no full text of the sourcecites [13] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“it has the potential both to regulate the axis-determining activity of LEF-1/TCF and to modulate other potential functions of LEF-1/TCF at later stages of development, such as neural patterning or mesoderm development (11).”
What the sources say
- Not checked — no full text of the sourcecites [11] source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Mechanistically, NLK directly interacts with and phosphorylates TCF-4.”
What the sources say
- Not checked — no full text of the sourcecites [13] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Such regulation of DNA binding by phosphorylation of sequence-specific transcription factors has been well documented in several cases and can act both positively and negatively (3).”
What the sources say
- Not checked — no full text of the sourcecites [3] source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
In mammalian cells, the relationships among NLK, β-catenin, and LEF-1/TCF are not well understood.
“On the other hand, in mammalian cells, the relationships among NLK, β-catenin, and LEF-1/TCF are not well understood.”
The paper relies on this without support.
The LEF-1 protein contains a COOH-terminal HMG DNA-binding domain and an NH2-terminal β-catenin-binding domain.
“The LEF-1 protein contains a COOH-terminal HMG DNA-binding domain and an NH2-terminal β-catenin-binding domain (Fig. 3A).”
The paper relies on this without support.
The components of the Wnt pathway (β-catenin, LEF-1/TCF, NLK) are conserved in vertebrates.
“These components are conserved in vertebrates.”
The paper relies on this without support.
In the early C. elegans embryo, Wnt signaling controls anterior-posterior cell polarity in the EMS blastomere.
“In the early C. elegans embryo, Wnt signaling controls anterior-posterior cell polarity in the EMS blastomere.”
The paper relies on this without support.
The β-catenin-related factor WRM-1 and the NLK-related kinase LIT-1 are effectors of Wnt signaling in the early C. elegans embryo.
“The β-catenin-related factor WRM-1 and the NLK-related kinase LIT-1 are effectors of this signaling pathway.”
The paper relies on this without support.
C. elegans Wnt signaling controls anterior-posterior cell polarity in postembryonic T blast cells.
“C. elegans Wnt signaling also controls anterior-posterior cell polarity in postembryonic T blast cells.”
The paper relies on this without support.
In many cases in which phosphorylation inhibits DNA binding, the phosphorylation sites are located either within or near the DNA-binding domain.
“In many cases in which phosphorylation inhibits DNA binding, the phosphorylation sites are located either within or near the DNA-binding domain.”
The paper relies on this without support.
In such cases, phosphorylation interferes with DNA binding by electrostatic repulsion between phosphate groups on the protein and the DNA.
“In such cases, it is likely that phosphorylation interferes with DNA binding by electrostatic repulsion between phosphate groups on the protein and the DNA.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In 293 cells, Flag-NLK suppressed reporter gene expression, a finding in agreement with previous reports.17), 34)”
From Mammalian Nemo-like kinase enhances .BETA.-catenin-TCF transcription activity in human osteosarcoma and neuroblastoma cells (2007) · cites this paper as [34]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Ishitani et al. suggested that DNA binding of LEF1 decreased with its phosphorylation at threonine 155 and serine 166 by overexpression of NLK.17), 34)”
From Mammalian Nemo-like kinase enhances .BETA.-catenin-TCF transcription activity in human osteosarcoma and neuroblastoma cells (2007) · cites this paper as [34]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In vertebrates, NLK is considered to be a negative regulator of the Wnt signalling pathway.”
From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [17]
The cited source says what the claim attributes to it.
In the citing paper
“This phosphorylation prevents DNA binding of the β-catenin-TCF4 complex and limits β-catenin-mediated target gene transcription through TCF/LEF [16,17].”
From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [17]
The cited source says what the claim attributes to it.
In the citing paper
“Previous studies showed that NLK can regulate the transcriptional activity of the β-catenin-LEF/TCF complex by directly phosphorylating TCF4.”
From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [17]
The cited source says what the claim attributes to it.
In the citing paper
“NLK-KN is a lysine to methionine substitution at residue 155 (K155M) and is defective for kinase activity (Ishitani et al., 2003; Ishitani et al., 2011).”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Ishitani et al., 2003
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Mutations are said both to abolish and to leave residual phosphorylation
MinorThe discussion says mutation of the identified sites abrogated NLK-mediated phosphorylation, but the results explicitly report weak phosphorylation of both mutant proteins.
“Site-directed mutagenesis of these conserved serine and threonine residues abrogated NLK-mediated phosphorylation in vitro and in vivo.”
“The fact that some weak phosphorylation was still observed with the LEF-1(2A) and TCF-4(2V) mutant forms suggests that LEF-1 and TCF-4 may contain additional NLK phosphorylation sites.”
Citations
Cites
Functional interaction of β-catenin with the transcription factor LEF-1
Behrens, J., von Kries, J. P., Kühl, M., Bruhn, L., Wedlich, D., Grosschedl, R., & Birchmeier, W. (1996) · Nature · doi:10.1038/382638a0 · Cited by 2,912
β‐catenin is a target for the ubiquitin–proteasome pathway
Aberle, H., Bauer, A., Stappert, J., Kispert, A., & Kemler, R. (1997) · The EMBO Journal · doi:10.1093/emboj/16.13.3797 · Cited by 2,586
Wnt signaling: a common theme in animal development
Cadigan, K. M., & Nusse, R. (1997) · Genes & Development · doi:10.1101/gad.11.24.3286 · Cited by 2,567
XTcf-3 Transcription Factor Mediates β-Catenin-Induced Axis Formation in Xenopus Embryos
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Regulation of transcription by MAP kinase cascades
Treisman, R. (1996) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(96)80067-6 · Cited by 1,296
Wnt Signaling in Oncogenesis and Embryogenesis--a Look Outside the Nucleus
Peifer, M., & Polakis, P. (2000) · Science · doi:10.1126/science.287.5458.1606 · Cited by 1,253
Ikeda, S., Kishida, S., Yamamoto, H., Murai, H., Koyama, S., & Kikuchi, A. (1998) · The EMBO Journal · doi:10.1093/emboj/17.5.1371 · Cited by 1,248
Drosophila Tcf and Groucho interact to repress Wingless signalling activity
Cavallo, R. A., Cox, R. T., Moline, M. M., Roose, J., Polevoy, G. A., Clevers, H., Peifer, M., & Bejsovec, A. (1998) · Nature · doi:10.1038/26982 · Cited by 730
Signal Transduction and the Control of Gene Expression
Brivanlou, A. H., & Darnell, J. E. (2002) · Science · doi:10.1126/science.1066355 · Cited by 699
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Wnt Signaling and Cardiac Differentiation
Flaherty, M. P., Kamerzell, T. J., & Dawn, B. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-398459-3.00007-1 · Cited by 41
He, X., Tan, Z.-L., Mou, Q.-L., Liu, F., Liu, S., Yu, C.-W., Zhu, J., Lv, L.-Y., Zhang, J., Wang, S., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1591 · Cited by 34
“The overexpression of NLK inhibits TCF/LEF-mediated transcription in both HeLa and HEK293 cells (34, 43, 44), whereas NLK positively regulates Wnt/b-catenin signaling by phosphorylating LEF1 in mouse neuroblastoma neuro-2a and rat pheochromocytoma tumor PC12 cells, as well as in zebrafish midbrain neural progenitor ce…”
BackgroundZhang, W., Wang, N., Zhang, T., Wang, M., Ge, W., & Wang, X. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.686805 · Cited by 40
“…a conserved pineal gland secretory product, which has been documented for more than 60 years is known to regulate many physiological events, such as circadian rhythmicity, seasonal adaptation, and reproductive changes (Johnston and Skene, 2015; Slominski et al., 2018).”
BackgroundClinical and biological significance of Nemo-like kinase expression in glioma
Cui, G., Li, Z., Shao, B., Li, Z., Zhou, Y., Lü, T., Wang, J., Shi, X., Wang, J., Zuo, G., et al. (2010) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2010.05.037 · Cited by 35
NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling
Masoumi, K. C., Daams, R., Sime, W., Siino, V., Ke, H., Levander, F., & Massoumi, R. (2017) · Molecular Biology of the Cell · doi:10.1091/mbc.e16-07-0547 · Cited by 35
“Previously it was shown that Lef1 phosphorylation by NLK prevents the binding of Lef1 to the promoter/DNA (Ishitani et al., 2003).”
BackgroundInfluentialDazap2 modulates transcription driven by the Wnt effector TCF-4
Lukáš, J., Mazna, P., Valenta, T., Doubravská, L., Pospíchalová, V., Vojtěchová, M., Fafílek, B., Ivánek, R., Plachý, J., Novák, J., et al. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp179 · Cited by 34
“Interestingly, the NLK phosphorylation sites in Tcfs are located just proximal to the region indispensable for Dazap2 binding ( 59 ).”
BackgroundNegative regulation of Wnt signalling by HMG2L1, a novel NLK‐binding protein
Yamada, M., Ohkawara, B., Ichimura, N., Hyodo‐Miura, J., Urushiyama, S., Shirakabe, K., & Shibuyà, H. (2003) · Genes to Cells · doi:10.1046/j.1365-2443.2003.00666.x · Cited by 33
“Then, we investigated whether xHMG2L1 expression would affect Wnt/β-catenin-mediated transcriptional activity in mammalian cells, similar to mNLK ( Ishitani et al. 1999, 2003 ).”
BackgroundMethodInfluentialGenome-wide identification of phospho-regulators of Wnt signaling inDrosophila
Swarup, S., Pradhan‐Sundd, T., & Verheyen, E. M. (2015) · Development · doi:10.1242/dev.116715 · Cited by 33
“, 2011), TOPFLASH, FOPFLASH, or Renilla luciferase (Ishitani et al., 2003) using Polyfect Reagent (Qiagen) and harvested 36-48 h post-transfection.”
MethodTAB2 Scaffolds TAK1 and NLK in Repressing Canonical Wnt Signaling
Li, M., Wang, H., Huang, T., Wang, J., Ding, Y., Li, Z., Zhang, J., & Li, L. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.083246 · Cited by 32
TCF4 Is a Molecular Target of Resveratrol in the Prevention of Colorectal Cancer
Jeong, J. B., Lee, J., & Lee, S. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms160510411 · Cited by 31
“TAK1 (transforming growth factor β-activated kinase 1) and MAP (mitogen-activated protein) kinase-related Nemo-like kinase (NLK) phosphorylates TCF on two serine/threonine residues and inhibited DNA binding by the β-catenin/TCF4 complex [33].”
BackgroundTogi, S., Ikeda, O., Kamitani, S., Nakasuji, M., Sekine, Y., Muromoto, R., Nanbo, A., Oritani, K., Kawai, T., Akira, S., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.189829 · Cited by 32
Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1
Ju, H., Kokubu, H., Todd, T. W., Kahle, J. J., Kim, S., Richman, R., Chirala, K., Orr, H. T., Zoghbi, H. Y., & Lim, J. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.3465-12.2013 · Cited by 31
“NLK-KN is a lysine to methionine substitution at residue 155 (K155M) and is defective for kinase activity (Ishitani et al., 2003; Ishitani et al., 2011).”
Feng, Y., Xie, N., Inoue, F., Fan, S., Saskin, J., Zhang, C., Zhang, F., Hansen, M. E. B., Nyambo, T., Mpoloka, S. W., et al. (2024) · Nature Genetics · doi:10.1038/s41588-023-01626-1 · Cited by 33
Expression of NLK and Its Potential Effect in Ovarian Cancer Chemotherapy
Zhang, Y., Chen, P., Wu, G., Wang, Y., Liu, R., Yang, S., He, S., He, F., Yuan, Q., Huang, Y., et al. (2011) · International Journal of Gynecological Cancer · doi:10.1097/igc.0b013e3182262030 · Cited by 30
Human immunodeficiency virus type 1 Tat prevents dephosphorylation of Sp1 by TCF-4 in astrocytes
Rossi, A., Mukerjee, R., Ferrante, P., et al. (2006) · Journal of General Virology · doi:10.1099/vir.0.81691-0 · Cited by 30
Yu, H.-C., Wu, T., Chen, M., Liu, S., Chen, J., & Lin, K. M.-C. (2010) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.9 · Cited by 32
Nemo is required in a subset of photoreceptors to regulate the speed of ommatidial rotation
Fiehler, R. W., & Wolff, T. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.10.034 · Cited by 26
Ubiquitin C-terminal hydrolase37 regulates Tcf7 DNA binding for the activation of Wnt signalling
Han, W., Lee, H., & Han, J. (2017) · Scientific Reports · doi:10.1038/srep42590 · Cited by 27
González, A., Manosalva, I., Liu, T., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053323 · Cited by 26
“The expression plasmids for NICD [11], Tbx6, T [12], human LEF1 [13] and constitutively active Ctnnb1 (S37A mutation) [14] were kind gifts of the authors.”
BackgroundExpression of Nemo-like kinase after spinal cord injury in rats
Xu, D., Zhao, W., Pan, G., Qian, M., Zhu, X., Liu, W., Cai, G., & Cui, Z.-M. (2014) · Journal of Molecular Neuroscience · doi:10.1007/s12031-013-0191-5 · Cited by 22
Tian, S., Liu, W., Pan, Y., & Zhan, S. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.11.101 · Cited by 24
Wnt signaling through T-cell factor phosphorylation
Sokol, S. Y. (2011) · Cell Research · doi:10.1038/cr.2011.86 · Cited by 24
M-cadherin-inhibited phosphorylation of ß-catenin augments differentiation of mouse myoblasts
Wang, Y., Mohamed, J. S., & Alway, S. E. (2012) · Cell and Tissue Research · doi:10.1007/s00441-012-1515-4 · Cited by 23
“…it can modify the activity of the T cell factor/lymphoid enhancer factor (TCF/LEF) family of DNA-binding proteins (Gottardi and Gumbiner 2001; Ishitani et al. 2003), and it is a central structural adaptor protein linking cadherins to the actin cytoskeleton in intercellular adherens…”
BackgroundTargeting the Wnt Pathway in Cancer
Goss, K. H., & Kahn, M. R. (2011) · Springer eBooks · doi:10.1007/978-1-4419-8023-6 · Cited by 23
Satoh, K., Ohnishi, J., Sato, A., Takeyama, M., Iemura, S., Natsume, T., & Shibuyà, H. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01481-07 · Cited by 22
“NLK functions downstream of transforming growth factor -activated kinase 1, a member of the mitogen-activated protein kinase (MAPK) kinase kinase family (15, 29); Wnt1 ( 14 ); and Wnt5a (16).”
BackgroundKe, H., Masoumi, K. C., Ahlqvist, K., Seckl, M. J., Rydell-Törmänen, K., & Massoumi, R. (2016) · Scientific Reports · doi:10.1038/srep23987 · Cited by 22
Nuclear Dishevelled: An enigmatic role in governing cell fate and Wnt signaling
Boligala, G. P., Yang, M. V., van Wunnik, J. C., & Pruitt, K. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2022.119305 · Cited by 22
Gupta, K., Kuznetsova, I., Klimenkova, O., Klimiankou, M., Meyer, J., Moore, M. A. S., Zeidler, C., Welte, K., & Skokowa, J. (2014) · Blood · doi:10.1182/blood-2012-09-456889 · Cited by 22
Elfert, S., Weise, A., Bruser, K., Biniossek, M. L., Jägle, S., Senghaas, N., & Hecht, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061867 · Cited by 20
“Future experiments involving TCF4 variants with additional substitutions at phospho-acceptor sites and coexpression of TNIK, NLK or HIPK2 should help to clarify whether there are any reciprocal effects between acetylation and phosphorylation of TCF4 proteins.”
BackgroundInfluentialMorillo, S. A., Braid, L. R., Verheyen, E. M., & Rebay, I. (2012) · Developmental Biology · doi:10.1016/j.ydbio.2012.02.030 · Cited by 24
“NLKs block activation of Wnt/Wg target genes (Zeng and Verheyen, 2004) by phosphorylating T-cell factor (TCF) and inhibiting the DNA-binding ability of the beta-catenin/TCF complexes (Ishitani et al., 1999; Ishitani et al., 2003).”
BackgroundShaw-Hallgren, G., Chmielarska Masoumi, K., Zarrizi, R., Hellman, U., Karlsson, P., Helou, K., & Massoumi, R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096506 · Cited by 21
“Upon activation, NLK can phosphorylate several proteins essential for the regulation of different signaling pathways, such as Wnt/b-catenin [6,7,9,10], Notch [11,12], and Smad [13].”
BackgroundZanotti, S., & CANALIS, E. M. (2011) · Journal of Cellular Biochemistry · doi:10.1002/jcb.23365 · Cited by 22
“In immortalized human cell culture systems, Nlk is activated by the non-canonical WNT Ca2þ pathway, resulting in phosphorylation and degradation of Tcf and inhibition of the canonical WNT signaling pathway [Ishitani et al., 2003; Smit et al., 2004; Yamada et al., 2006; Li et al., 2010].”
BackgroundNemo-Like Kinase in Development and Diseases: Insights from Mouse Studies
Daams, R., & Massoumi, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239203 · Cited by 21
“This phosphorylation prevents DNA binding of the β-catenin-TCF4 complex and limits β-catenin-mediated target gene transcription through TCF/LEF [16,17].”
BackgroundOhnishi, E., Goto, T., Sato, A., Kim, M. S., Iemura, S.-I., Ishitani, T., Natsume, T., Ohnishi, J., & Shibuyà, H. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00576-09 · Cited by 21
“NLK functions downstream of transforming growth factor -activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK or MAP3K) family (10, 22), Wnt1 (9), and Wnt5a (8).”
BackgroundMethodSelf-citationIntegration of anterior neural plate patterning and morphogenesis by the Wnt signaling pathway
Cavodeassi, F. (2013) · Developmental Neurobiology · doi:10.1002/dneu.22135 · Cited by 19
“In addition, the TF Hesx1, expressed in the forebrain, is required together with TCF3 to maintain the repressed state of Wnt/b-catenin targets (Andoniadou et al., 2011).”
Wnt signaling during tooth replacement in zebrafish (Danio rerio): pitfalls and perspectives
Huysseune, A., Soenens, M., & Elderweirdt, F. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00386 · Cited by 19
“Likewise, once the replacement teeth have been initiated in positions 3V and 5V (i.e., teeth 3V2 and 5V2), they display epithelial expression (Figure 3F).”
BackgroundNifuji, A., Ideno, H., Ohyama, Y., Takanabe, R., Araki, R., Abe, M., Noda, M., & Shibuyà, H. (2010) · Experimental Cell Research · doi:10.1016/j.yexcr.2010.01.023 · Cited by 20
Chen, X., Li, W., Chen, T., Ren, X., Zhu, J., Hu, F., Luo, J., Xing, L., Zhou, H., Sun, J., et al. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.09.056 · Cited by 20
The emerging role of Nemo-like kinase (NLK) in the regulation of cancers
Huang, Y., Yang, Y., He, Y., & Li, J. (2015) · Tumor Biology · doi:10.1007/s13277-015-4159-7 · Cited by 19
A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/β-catenin signalling pathway
Mittag, S., Valenta, T., Weiske, J., Bloch, L., Klingel, S., Gradl, D., Wetzel, F., Chen, Y., Petersen, I., Basler, K., et al. (2016) · Cell Discovery · doi:10.1038/celldisc.2015.39 · Cited by 19
Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality
Shao, Y., Zielinski, E., Childress, P., Adaway, M., Misra, J., Klunk, A. J., Burr, D. B., Wek, R. C., Mosley, A. L., Liu, Y., et al. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00343.2018 · Cited by 20
Su, H., Sureda-Gómez, M., Rabaneda‐Lombarte, N., Gelabert, M., Xie, J., Wu, W., & Adell, T. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1007030 · Cited by 18
The aberrant expression or disruption of desmocollin2 in human diseases
Sun, C., Wang, L., Yang, X., Jiang, Y.-H., & Guo, X. (2019) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2019.03.041 · Cited by 18
Nemo-like Kinase (NLK) Involves in Neuronal Apoptosis after Traumatic Brain Injury
Li, Z., Cui, G., Wang, J., Yu, Z., Li, Z., & Lv, Z. (2011) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-011-9766-2 · Cited by 18
“NLK mainly expresses in neural tissues, and has important roles in neural development and maintenance, but the precise mechanisms have not been fully characterized (Ishitani et al. 2003).”
García‐Corzo, L., Calatayud-Baselga, I., Casares-Crespo, L., Mora‐Martínez, C., Escribano-Saiz, J. J., Hortigüela, R., Asenjo-Martínez, A., Jordán‐Pla, A., Ercoli, S., Flames, N., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.912319 · Cited by 17
“…upon Wnt signalling activation by the HIPK2 kinase in the HMG box domain (Hikasa et al., 2010; Hikasa and Sokol, 2011) and in the central region by nemo-like kinase (Ishitani et al., 2003), a modification that triggers its ubiquitination and proteasomal degradation (Yamada et al., 2006).”
BackgroundWnt Signaling in Lymphopoiesis
Timm, A., & Grosschedl, R. (2005) · Springer eBooks · doi:10.1007/3-540-26363-2_10 · Cited by 17
NLK suppresses MAVS-mediated signaling in black carp antiviral innate immunity
Chen, Z., Cao, Y., Huang, J., Tan, Y., Wei, J., Xiao, J., Zou, J., & Feng, H. (2021) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2021.104105 · Cited by 16
Lei, L., Wang, Y., Zheng, Y.-W., Fei, L., Shen, H.-Y., Li, Z.-H., Huang, W.-J., Yu, J.-H., & Xu, H.-T. (2019) · Current Cancer Drug Targets · doi:10.2174/1568009618666181119150521 · Cited by 11
Duan, R., Hijazi, H., Güleç, E. Y., Eker, H. K., Costa, S. R., Şahin, Y., Ocak, Z., Işıkay, S., Ozalp, O., Bozdoğan, S. T., et al. (2022) · Human Genetics and Genomics Advances · doi:10.1016/j.xhgg.2022.100132 · Cited by 15
“For human WNT signaling, we also reported limb findings of bilateral foot oligodactyly and left-hand syndactyly in the individual with a de novo, likely damaging variant allele of Nemo-like kinase (NLK), an inhibitor of the WNT/b-catenin signaling pathway (Figure S7; Supplemental Note).(79,80) These clinical observati…”
Exendin-4 promotes pancreatic β-cell proliferation via inhibiting the expression of Wnt5a
Wu, X., Liang, W., Guan, H., Liu, J., Liu, L., Li, H., He, X., Zheng, J., Chen, J., Cao, X., et al. (2016) · Endocrine · doi:10.1007/s12020-016-1160-x · Cited by 15
Sravani, A. N. K. V., & Thomas, J. (2025) · Heliyon · doi:10.1016/j.heliyon.2025.e41964 · Cited by 15
RetractedBanerjee, M., & Rajeswari, V. D. (2022) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2022.103901 · Cited by 14
Oxidative Stress-Dependent Regulation of Forkhead Box O4 Activity by Nemo-Like Kinase
Szypowska, A. A., de Ruiter, H., Meijer, L. A. T., Smits, L. M. M., & Burgering, B. M. T. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3243 · Cited by 13
“NLK, which subsequently binds to and phosphorylates TCF. NLK-mediated phosphorylation of TCF impairs its ability to bind DNA and thereby decreases its transcriptional activity (21).”
Ajorloo, F., Vaezi, M., Saadat, A., Safaee, S. R., Gharib, B., Ghanei, M., Siadat, S. D., Vaziri, F., Fateh, A., Pazhouhandeh, M., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0183969 · Cited by 13
Wnt/β‐catenin‐mediated transcriptional regulation
Parker, D. S., Blauwkamp, T. A., & Cadigan, K. M. (2007) · Advances in developmental biology · doi:10.1016/s1574-3349(06)17001-5 · Cited by 14
Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development.
Cho, S.-J., Cha, B., Kwon, O.-S., Lim, J.-S., Shin, D.-M., Han, D., Ishitani, T., Jho, E., Fornace, A., & Cha, H.-J. (2017) · Biochimica et Biophysica Acta - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.01.028 · Cited by 12
Self-citationOTUD7B Activates Wnt Signaling Pathway through the Interaction with LEF1
Lee, Y., Piao, H., & Kim, J. (2023) · Biomolecules · doi:10.3390/biom13061001 · Cited by 11
Muñoz, V. F. L., Ruiz, C., Pérez‐Alonso, M., Mlodzik, M., & Paricio, N. (2013) · Developmental Biology · doi:10.1016/j.ydbio.2013.02.006 · Cited by 11
“…domain of Notch1 (Notch1-ICD) or Nuclear Factor-κβ (NF-κβ) through phosphorylation of its cofactor CREB binding protein (CBP) (Ishitani et al., 2010; Ishitani et al., 2003; Ishitani et al., 1999; Kanei-Ishii et al., 2004; Kojima et al., 2005; Meneghini et al., 1999; Ohkawara et al., 2004; Shi…”
BackgroundO’Connor, S. L., Markovina, S. S., & Miyamoto, S. (2005) · Experimental Cell Research · doi:10.1016/j.yexcr.2005.02.015 · Cited by 11
Dahm, K., Vijayarangakannan, P., Wollscheid, H.-P., Schild, H., & Rajalingam, K. (2024) · FEBS Journal · doi:10.1111/febs.17283 · Cited by 11
Yin, X., Ren, Y., Luo, W., Liao, M., Huang, L., Zhuang, X., Liu, Y., & Wang, W. (2022) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2022.104378 · Cited by 10
Braid, L. R., Lee, W., Uetrecht, A. C., Swarup, S., Papaianni, G., Heiler, A., & Verheyen, E. M. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2010.04.008 · Cited by 10
xBtg-x regulates Wnt/β-Catenin signaling during early Xenopus development
Wessely, O., Kim, J. I., Tran, U., Fuentealba, L. C., & Robertis, E. M. D. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.03.033 · Cited by 12
“Nlk is a serine/threonine protein kinase that negatively controls h-Catenin-dependent transcription by regulating the DNA-binding activity of the h-Catenin/TCF complex in the nucleus (Ishitani et al., 1999; Meneghini et al., 1999; Ishitani et al., 2003).”
BackgroundZhang, X.-W., Chen, S.-Y., Xue, D., Xu, H., Yang, L., Xu, H., & Wang, E. (2015) · PubMed Central · Cited by 9
Human SMAD4 is phosphorylated at Thr9 and Ser138 by interacting with NLK
Shi, Y., Ye, K., Wu, H., Sun, Y., Shi, H., & Huo, K. (2009) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-009-0230-2 · Cited by 8
“In human Wnt signaling pathway, activated NLK can directly bind and phosphorylate LEF-1/TCF, contributing to the down-regulation of LEF-1/TCF transcriptional activity [17].”
BackgroundNemo‐Like Kinase Regulates Postnatal Skeletal Homeostasis
Canalis, E., Kranz, L., & Zanotti, S. (2014) · Journal of Cellular Physiology · doi:10.1002/jcp.24625 · Cited by 7
“Recently, Nlk was found to play a critical role in the regulation of diverse signaling pathways, in particular theWnt/b-catenin, BMP/Smad and the Notch signaling pathways (Ishitani et al., 2003, 2010; Zeng et al., 2007).”
BackgroundTomimaru, Y., Koga, H., Shin, T. H., Xu, C. Q., Wands, J. R., & Kim, M. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.03.031 · Cited by 8
“NLK, which is a serine/ threonine kinase originally described in Drosophila, negatively regulates the Wnt/b-catenin signaling pathway in response to transforming growth factor-b-activated kinase 1 and similarly to HIPK2, inhibits the interaction of b-catenin/TCF-4 protein complex with DNA [36,37,39].”
MethodInfluentialDeletion of Nemo-like Kinase in T Cells Reduces Single-Positive CD8+ Thymocyte Population
Daams, R., Sime, W., Leandersson, K., Sitnicka, E., & Massoumi, R. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.2000109 · Cited by 7
YASUDA, J., & ICHIKAWA, H. (2007) · Proceedings of the Japan Academy, Series B · doi:10.2183/pjab.83.16 · Cited by 6
TCF/LEF-mediated transcriptional regulation in the canonical Wnt pathway
Takano, C., & Higuchi, Y. (2025) · Current Molecular Pharmacology · doi:10.1016/j.cmp.2025.09.004 · Cited by 6
Our evolving view of Wnt signaling in C. elegans
Robertson, S. M., & Lin, R. (2012) · Worm · doi:10.4161/worm.19156 · Cited by 6
“In vertebrates, NLK phosphorylation of certain TCFs has also been shown to inhibit their DNA-binding ability.(57,58) Therefore, although the mechanistic details differ between the worm and vertebrates with respect to how NLK regulates TCF proteins, the end result appears to be the same—NLK phosphorylation of a TCF res…”
BackgroundFerrando-Marco, M., & Barkoulas, M. (2025) · Development · doi:10.1242/dev.204546 · Cited by 2
Protein Kinases Involved in the Regulation of Wnt/β-catenin Signaling
Shin, E., Park, E. C., Hong, Y., & Kim, G. (2013) · Journal of Life Science · doi:10.5352/jls.2013.23.7.947 · Cited by 5
“NLK의 경우 LEF1과 TCF4에 결합하여 TCF/β-catenin complex가 DNA에 결합하는 것을 억제하며, complex를 핵 밖으로 내보내거나 LEF/TCF 단백질의 분해를 유도하여 Wnt 신호의 활성을 감소시키는 역할을 한다[21, 22].”
Tai, J., Rao, Y., Fang, J., et al. (2015) · Molecular Medicine Reports · doi:10.3892/mmr.2015.4189 · Cited by 5
Regulation of Natural Products on Wnt/β-Catenin Signaling Pathway in Diseases
Zheng, G., Lin, S., Wang, S., Yan, Y., & Zheng, D. (2025) · The American Journal of Chinese Medicine · doi:10.1142/s0192415x25500272 · Cited by 4
Johnson, M. L. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-373884-4.00013-6 · Cited by 4
KSHV vPK inhibits Wnt signaling via preventing interactions between β-catenin and TCF4
Cha, S., Kang, M.-S., & Seo, T. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.02.089 · Cited by 4
Korswagen, H. C. (2007) · Advances in developmental biology · doi:10.1016/s1574-3349(06)17003-9 · Cited by 4
Dab2 (Disabled-2), an adaptor protein, regulates self-renewal of hair follicle stem cells
Roy, S., Mehta, D., Paradkar, A., Chovatiya, G. L., & Waghmare, S. K. (2024) · Communications Biology · doi:10.1038/s42003-024-06047-2 · Cited by 4
Górka, J., & Miękus, K. (2025) · Discover Oncology · doi:10.1007/s12672-025-02228-5 · Cited by 4
“This involves proteins such as Chibby, ICAT (inhibitors of β-catenin and TCF4), and NLK (Nemo-like kinases), which ultimately disrupt the regulation of Wnt target genes [85–88].”
Wnt/β-Catenin Signaling and Oral Cancer Metastasis
Zhou, G. (2009) · Springer eBooks · doi:10.1007/978-1-4419-0775-2_11 · Cited by 4
PMA-induced GCMa phosphorylation stimulates its transcriptional activity and degradation
Yasui, Y., Miyazawa, D., Ueda, H., et al. (2012) · Biomedical Research · doi:10.2220/biomedres.33.217 · Cited by 3
“The transcriptional activity of GCMa increases through the PKC- and MEK/ERK-dependent pathway in the PMA-treated cells It has been shown that post-translational modification of transcription factor is related in its transcriptional activity (14, 21, 34, 41).”
BackgroundWnt/β-catenin signaling pathway and its role in hepatocellular carcinoma
Zhang, X., Yu, L., & Lu, Y. (2008) · Frontiers of Medicine · doi:10.1007/s11684-008-0042-x · Cited by 3
“kinase-related Nemo-like kinase (NLK) [76,77].”
Contreras, O., Soliman, H., Théret, M., Rossi, F. M. V., & Brandan, E. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.01.05.895334 · Cited by 3
Targeting Wnt Signalling in Cancer
Holik, A. Z., & Clarke, A. R. (2010) · Springer eBooks · doi:10.1007/978-1-4419-8023-6_8 · Cited by 1
“phosphorylate TCF and thus target it for ubiquitylation and subsequent degradation, effectively inhibiting TCF-mediated transcription ( Ishitani et al. 2003b; Yamada et al. 2006).”
BackgroundRegulation of canonical Wnt/β-catenin pathway in the nucleus
Han, W., & Wang, H. (2014) · Chinese Science Bulletin · doi:10.1007/s11434-014-0489-x · Cited by 1
Ishitani, T. (2015) · Springer eBooks · doi:10.1007/978-4-431-55561-2_20 · Cited by 1
Self-citationContext-Dependent Bidirectional Modulation of Wnt/β-Catenin Signaling
Ishitani, T. (2014) · Springer eBooks · doi:10.1007/978-4-431-54634-4_16 · Cited by 1
Self-citationTransformation of Pluripotency States during Morphogenesis of Mouse and Human Epiblast
Abdyev, V. K., Алпеева, Е. В., Kalistratova, E. N., Vorotelyak, E. A., & Vasiliev, A. V. (2023) · Russian Journal of Developmental Biology · doi:10.1134/s1062360423050028 · Cited by 1
“It seems that, in preimplantation mouse development, WNT uses noncanonical pathways, such as Wnt/Ca +2 (Harwood et al., 2008) and effector molecules SAMK2A/TAK1/NLK, which inhibit the binding of β -catenin-TCF/LEF to DNA by phosphorylation of TCF/LEF (Ishitani et al., 1999, 2003).”
Wnt signaling and bone cell activity
Williams, B. O., & Johnson, M. L. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814841-9.00008-7 · Cited by 1
Characterizing the roles of Memo in TGFߠSignalling
Sosu-Sedzorme, W. (2004) · Summit (Simon Fraser University)
GENE EXPRESSION ANALYSIS IN MEASLES VIRUS RESEARCH
Zilliox, M. J. (2007)
Molecular Mechanisms of Wnt Pathway Specificity
Schambony, A., Zaman, G. J. R., & Verkaar, F. (2014) · Wiley eBooks · doi:10.1002/9781118444122.ch7
Members of the T-Cell Factor Family of DNA-Binding Proteins and Their Roles in Tumorigenesis
Hecht, A. (2004) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-18932-6_5
Comer, S. B. (2007) · UA Campus Repository (The University of Arizona)
Du, H., Wang, L., Zheng, X., et al. (2015) · Journal of Hard Tissue Biology · doi:10.2485/jhtb.24.169
McCutcheon, L. J. G. (2009) · University of the Witwatersrand, Johannesburg Institutional Repository on DSpace (University of the Witwatersrand, Johannesburg)
Maduro, M., Kasmir, J. J., Zhu, J., & Rothman, J. H. (2005)
Canonical Wnt Signaling in Hair and Mammary Gland Patterning and Development
Närhi, K. M. (2012) · Työväentutkimus Vuosikirja
The role of CD44 in Wnt/β-catenin signaling
Schmitt, M. (2014) · Repository KITopen (Karlsruhe Institute of Technology) · doi:10.5445/ir/1000043638
“Interestingly, the Wnt/calcium pathway interacts with the Wnt/β-catenin pathway (Ishitani et al., 2003a).”
Background
Metadata
- Authors
- Ishitani, T., Ninomiya-Tsuji, J., & Matsumoto, K.
- Affiliations
- Nagoya University (JP)
- Department of Molecular Biology, Graduate School of Science, Nagoya University, and CREST, Japan Science and Technology Corporation, Chikusa-ku, Nagoya 464-8602, Japan
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2003-02-01
- Volume
- 23
- Issue
- 4
- Pages
- 1379-1389
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC141159
- OpenAlex
- W2113359377
- Semantic Scholar
- c5bd5fdc22c48d8a897ece5568678314f28893e2
- Cited by
- 212
- References
- 38
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 4 · 2023: 3 · 2022: 6 · 2021: 3 · 2020: 6 · 2019: 6 · 2018: 3 · 2017: 8 · 2016: 7 · 2015: 11 · 2014: 14 · 2013: 11 · 2012: 13
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- Core Research for Evolutional Science and Technology
- 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 › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Keywords
- Nemo-like kinase, TCF4, Wnt/β-catenin signaling, β-catenin, transcriptional repression, MAPK signaling, TAK1, serine/threonine phosphorylation, transcriptional activity, protein-protein interaction
- MeSH terms
- MAP Kinase Kinase Kinase 7, Amino Acid Sequence, Cells, Cultured, Cytoskeletal Proteins, DNA-Binding Proteins, Humans, Molecular Sequence Data, Mutation, Phosphorylation, Proto-Oncogene Proteins, Serine, Threonine, Transcription Factors, Valine, Signal Transduction, Trans-Activators, Down-Regulation, Protein Serine-Threonine Kinases, Sequence Homology, Amino Acid, Amino Acid Substitution, Two-Hybrid System Techniques, Mitogen-Activated Protein Kinases, MAP Kinase Kinase Kinases, Zebrafish Proteins, Intracellular Signaling Peptides and Proteins, Wnt Proteins, beta Catenin, TCF Transcription Factors, Lymphoid Enhancer-Binding Factor 1, Transcription Factor 7-Like 2 Protein
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