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
Molenaar, M., van de Wetering, M., Oosterwegel, M., Peterson-Maduro, J., Godsave, S., Korinek, V., Roose, J., Destrée, O., & Clevers, H. (1996) · Cell · doi:10.1016/s0092-8674(00)80112-9 · Cited by 1,824
Wetering, M. L. V. D., Cavallo, R. A., Dooijes, D., van Beest, M., van Es, J. V., Loureiro, J., Ypma, A., Hursh, D., Jones, T. L., Bejsovec, A., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)81925-x · Cited by 1,347
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
Flagged first, then by citations
1 of the 38 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Shin T. H., 1999, Cell, 4, 275
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Items 201–212 of 212
Investigations into the Interaction between Src Kinase and Wnt Signaling
Tang, P. L. (2009) · Libraries and Cultural Resources (University of Calgary) · doi:10.11575/prism/14854
Wu, Y., Fu, Y., He, K., & Song, H. (2021) · Gene Reports · doi:10.1016/j.genrep.2021.101260
Ishitani, T., & Ishitani, S. (2016) · Springer eBooks · doi:10.1007/978-1-4614-6438-9_101750-1
Self-citationIshitani, T., & Ishitani, S. (2017) · Springer eBooks · doi:10.1007/978-3-319-67199-4_101750
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) · Онтогенез · doi:10.31857/s0475145023050026
Ferrando-Marco, M., & Barkoulas, M. (2024) · bioRxiv · doi:10.1101/2024.07.01.601538
“NLK-mediated Tcf/Lef phosphorylation can have positive or negative consequences on its activity depending on the cellular context 79–81 .”
BackgroundLi, K., Li, M., Zhongning, L. I. U., Yang, J., Li, J., & JIANG, T. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2025.167870
Research Progress of LEF1 Gene in Malignant Tumors
Zhao, Y., Pan, C., Yang, S., Xiao-ling, M., Yao, Y., Li, Z., Ma, Q., Wang, X., Wang, C., & Nie, Z. (2025) · Clinical Medicine Insights Oncology · doi:10.1177/11795549251371111
“The role of LEF-1 in tumors is dynamically regulated by various mechanisms, including phosphorylation 44 and m6A methylation, and is influenced by the activity of cofactors.”
LEF1 gene mutation impairs the intestinal barrier and causes diarrhea
Jie, J., Qiu, M., Liu, X., Zhang, Q., Xie, J. X., Geng, L., Gong, S. T., & Cheng, Y. (2026) · Molecular and Cellular Pediatrics · doi:10.1186/s40348-026-00240-5
“Within the Notch signaling pathway, LEF1 participates in epigenetic regulatory processes [17], whereas in the mitogen-activated protein kinase (MAPK) signaling pathway, NLK and ERK kinases phosphorylate LEF1, thereby dynamically modulating its transcriptional activity and protein stability [18].”
Colorectal Cancer and the Enigma Surrounding Non-Canonical Wnt Signaling
Kita, K. (2026) · Cancers · doi:10.3390/cancers18162618
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-18, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-18 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
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