Mammalian Nemo-like kinase enhances .BETA.-catenin-TCF transcription activity in human osteosarcoma and neuroblastoma cells
Open accessAbstract
Nemo-like kinase (NLK) is an evolutionarily conserved serine/threonine kinase and has been considered to be a suppressor of Wnt signaling in mammalian cells. Our study, however, has raised the possibility that NLK also functions as a Wnt signaling activator. In human osteosarcoma and neuroblastoma cell lines, NLK specifically enhanced β-catenin-TCF complex transcription activity. The effect required kinase activity of NLK and co-expression of the β-catenin ΔN (constitutive active mutant of β-catenin). The nuclear localization of Lymphoid enhancer factor 1 (LEF1) and β-catenin ΔN was not altered by NLK overexpression regardless of its effect on β-catenin-TCF complex activity. Reporter analysis using LEF1 mutants at known NLK target sites indicated that NLK may have different activation targets for β-catenin-TCF complex. Mutations in the potential NLK phosphorylation sites in β-catenin did not change its transcription activity either. Our results suggest that NLK positively regulates Wnt/β-catenin signaling in a cell type dependent manner through an unidentified mechanism.
AI snapshot
Written from the paper’s full text.
TL;DR
Mammalian Nemo-like kinase (NLK) enhanced β-catenin–TCF transcription activity in human osteosarcoma and neuroblastoma cell lines, in contrast to its suppressive effect in 293 epithelial cells. This activation required NLK kinase activity and co-expression of constitutively active β-catenin ΔN, but did not involve altered nuclear localization of LEF1/β-catenin or the tested conserved phosphorylation sites.
Key findings
- NLK activated the pTOPFLASH β-catenin–TCF reporter in SaOS-2 osteosarcoma and in Nh12 and NB39-nu neuroblastoma cells, but suppressed it in 293 epithelial cells; pFOPFLASH, a negative-control reporter, was not activated.
- Activation required NLK kinase activity: kinase-negative NLK mutants failed to enhance pTOPFLASH, and NLK did not activate pTOPFLASH without co-expressed β-catenin ΔN.
- NLK overexpression did not change nuclear localization of HA-LEF1 or MYC-β-catenin ΔN in either 293 or SaOS-2 cells.
- LEF1 mutants at conserved sites (T155A, S166A, 155/166AA, S132TSAA, TSAAS200A) and β-catenin ΔN mutants (S191A, S246A, S605A) did not abolish NLK-dependent pTOPFLASH activation, suggesting the tested phosphorylation sites are not required for this activation.
Methods
- Cell lines used: 293 (human kidney epithelial), SaOS-2 (human osteosarcoma), Nh12 and NB39-nu (human neuroblastoma).
- Dual-luciferase assays used pTOPFLASH/pFOPFLASH reporters with pRL-tk, effector plasmids for NLK isoforms, kinase-negative NLK, β-catenin ΔN, and LEF1 mutants; plasmid amounts were 0.1–0.3 μg/well depending on the experiment, and each experiment was performed at least twice in triplicate.
- Immunofluorescence was used to assess nuclear localization of HA-LEF1 and MYC-β-catenin ΔN with or without NLK-S in 293 and SaOS-2 cells.
Limitations
- The paper states that the mechanism by which NLK activates β-catenin–TCF is unidentified, and that it is unclear whether NLK plays a positive role in normal mammalian development.
- The paper states that the molecular basis for the differential effect of NLK among cell lines is an open question, including the possibility that NLK requires other factors absent from 293 cells.
- Evident from the text: conclusions rely on overexpression and reporter assays in cultured cell lines, with no direct identification of the relevant NLK substrate(s) or in vivo validation.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
5 of 20 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured
- Findingown data
Flag-NLK suppresses pTOPFLASH reporter gene expression in 293 cells.
“In 293 cells, Flag-NLK suppressed reporter gene expression, a finding in agreement with previous reports.17), 34)”
- Also stated in: § Discussion · plain
“NLK isoforms suppressed pTOPFLASH reporter to some degree in 293 cells.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [17] source
- cites [34] source
The Results (Fig. 6; page not supplied) report that NLK inhibited TOPFLASH reporter activity when coexpressed with Wnt-1 and LEF-1. But the reporter assay was performed in HeLa cells, not 293 cells; the paper describes Flag-NLK experiments in 293 cells for other purposes. (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Also stated in: § Discussion · plain
- Findingown data
NLK-S slightly reduces NF-κB and p53 reporter expression in SaOS-2 cells.
“NLK-S slightly reduced the expression of both reporters (Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
The transcription activity of the LEF1 155/166AA double mutant is similar to wild-type LEF1 even when NLK is co-expressed.
“The transcription activity of the 155/166AA double mutant was very similar to that of wild-type LEF1 even when NLK was co-expressed (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
LEF1 mutants T155A, S166A, and 155/166AA can induce pTOPFLASH reporter gene expression.
“Overexpression of the LEF1 mutants, T155A, S166A and 155/166AA, could induce pTOPFLASH reporter gene expression (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
NLK overexpression does not alter the nuclear localization of LEF1 or β-catenin ΔN in 293 or SaOS-2 cells.
“The nuclear localization of Lymphoid enhancer factor 1 (LEF1) and β-catenin ΔN was not altered by NLK overexpression regardless of its effect on β-catenin-TCF complex activity.”
- Also stated in: § NLK does not change the nuclear localization of LEF1 in either 293 cells or SaOS-2 cells · plain
“Co-expression with NLK did not alter the nuclear localization of either LEF1 or β-catenin ΔN in either 293 or SaOS-2 cells (Fig. 4A and B, respectively).”
- Also stated in: § Discussion · plain
“Nuclear localization of the LEF1 and β-catenin ΔN was not altered by the co-expression of NLK in either epithelial (293) or osteosarcoma cells.”
Quote in the paperSubstantial claim - Also stated in: § NLK does not change the nuclear localization of LEF1 in either 293 cells or SaOS-2 cells · plain
- Findingown data
Mutations in potential NLK phosphorylation sites in β-catenin do not change β-catenin ΔN transcription activity in SaOS-2 cells.
“Mutations in the potential NLK phosphorylation sites in β-catenin did not change its transcription activity either.”
- Also stated in: § β-catenin phosphorylation site mutations do not affect its transcription activation by NLK · plain
“mutational status of β-catenin ΔN at the phosphorylation sites did not alter its transcription activity by NLK overexpression in SaOS-2 cells.”
- Also stated in: § Discussion · plain
“mutational status of certain potential phosphorylation sites of β-catenin and LEF1 did not alter their transcription activity by NLK overexpression.”
Quote in the paperSubstantial claim - Also stated in: § β-catenin phosphorylation site mutations do not affect its transcription activation by NLK · plain
- Findingown data
NLK enhances β-catenin-TCF complex transcription activity in human osteosarcoma and neuroblastoma cell lines.
“In human osteosarcoma and neuroblastoma cell lines, NLK specifically enhanced β-catenin-TCF complex transcription activity.”
- Also stated in: § NLK enhances the transcription activity of the β-catenin-TCF complex in osteosarcoma and neuroblastoma cell lines · hedged
“NLK showed apparent induction of the reporter gene expression in SaOS-2 cells, suggesting that NLK enhances β-catenin-TCF transcription (Fig. 2A).”
- Also stated in: § NLK enhances the transcription activity of the β-catenin-TCF complex in osteosarcoma and neuroblastoma cell lines · plain
“overexpression of NLK caused activation of the pTOPFLASH in Nh12 and NB39-nu neuroblastoma cell lines in a kinase-dependent manner (Fig. 2C).”
Quote in the paperSubstantial claim- The authors state this as an assumption: NLK may play a positive role for Wnt signaling in mammalian cells.
- Also stated in: § NLK enhances the transcription activity of the β-catenin-TCF complex in osteosarcoma and neuroblastoma cell lines · hedged
- Findingown data
NLK-S suppresses pTOPFLASH reporter gene expression in 293 cells to a lesser degree than Flag-NLK.
“NLK-S also suppressed the reporter gene expression but to a lesser degree (Fig. 2A).”
Quote in the paperNot a substantial claim - Findingown data
pFOPFLASH reporter is not activated by NLK.
“Reporter gene analysis with pFOPFLASH, a negative control reporter for pTOPFLASH with mutant TCF/LEF binding sites, showed no activation, also indicating that NLK activates β-catenin-TCF transcription (Fig. 2B, right panel).”
- Also stated in: § Activation of β-catenin-TCF by NLK is not mediated by phosphorylation of the conserved Threonine 155 and Serine 166 sites in LEF1 · plain
“The activation of β-catenin-LEF1 complex by NLK was specific to pTOPFLASH, as the pFOPFLASH reporter was not activated (Fig. 5A).”
Quote in the paperSubstantial claim - Also stated in: § Activation of β-catenin-TCF by NLK is not mediated by phosphorylation of the conserved Threonine 155 and Serine 166 sites in LEF1 · plain
- Findingown data
The enhancement of β-catenin-TCF transcription activity by NLK requires co-expression of β-catenin ΔN.
“The effect required kinase activity of NLK and co-expression of the β-catenin ΔN (constitutive active mutant of β-catenin).”
- Also stated in: § NLK enhances the transcription activity of the β-catenin-TCF complex in osteosarcoma and neuroblastoma cell lines · hedged
“Both Flag-NLK and NLK-S failed to activate pTOPFLASH without β-catenin ΔN in SaOS-2 cells, indicating that NLK activates Wnt/β-catenin signaling through the β-catenin-TCF complex (Fig. 2B, left panel).”
- Also stated in: § Discussion · plain
“This enhancement of transcription activity by NLK is dependent of co-expression of β-catenin.”
Quote in the paperSubstantial claim - Also stated in: § NLK enhances the transcription activity of the β-catenin-TCF complex in osteosarcoma and neuroblastoma cell lines · hedged
- Findingown data
All NLK isoforms, regardless of N-terminal sequences, enhance β-catenin-TCF complex activity in SaOS-2 cells.
“Therefore, all NLK isoforms, regardless of their N-terminal sequences, enhanced β-catenin-TCF complex activity in SaOS-2 cells (Fig. 2A and B).”
Quote in the paperSubstantial claim - Findingown data
The enhancement of β-catenin-TCF transcription activity by NLK requires NLK kinase activity.
“The effect required kinase activity of NLK and co-expression of the β-catenin ΔN (constitutive active mutant of β-catenin).”
- Also stated in: § NLK enhances the transcription activity of the β-catenin-TCF complex in osteosarcoma and neuroblastoma cell lines · boosted
“The kinase-negative NLK mutants did not enhance the reporter gene expression (Fig. 2B, middle panel), thus showing that the enhancement of expression by NLK is kinase-dependent.”
- Also stated in: § NLK enhances the transcription activity of the β-catenin-TCF complex in osteosarcoma and neuroblastoma cell lines · plain
“overexpression of NLK caused activation of the pTOPFLASH in Nh12 and NB39-nu neuroblastoma cell lines in a kinase-dependent manner (Fig. 2C).”
Quote in the paperSubstantial claim - Also stated in: § NLK enhances the transcription activity of the β-catenin-TCF complex in osteosarcoma and neuroblastoma cell lines · boosted
- Findingown data
Additional LEF1 mutations S132TSAA and TSAAS200A do not affect pTOPFLASH activity with NLK and β-catenin ΔN co-expression.
“Furthermore, additional mutations in other potential phosphorylation sites (S132A/T155A/S166A triple mutant as S132TSAA and T155A/S166A/S200A triple mutant as TSAAS200A) also did not affect pTOPFLASH activity with NLK and β-catenin ΔN co-expression (Fig. 5B).”
Quote in the paperSubstantial claim - Interpretationown data
The conserved phosphorylation sites in TCF/LEF are not the target for transcription activation by NLK.
“These results indicated that the conserved phosphorylation sites in TCF/LEF would not be the target for transcription activation by NLK.”
Quote in the paperSubstantial claim - Interpretationown data
NLK activates Wnt/β-catenin signaling through the β-catenin-TCF complex.
“Both Flag-NLK and NLK-S failed to activate pTOPFLASH without β-catenin ΔN in SaOS-2 cells, indicating that NLK activates Wnt/β-catenin signaling through the β-catenin-TCF complex (Fig. 2B, left panel).”
Quote in the paperSubstantial claim - Interpretationown data
The activation mechanism of β-catenin-TCF complex by NLK may be different from that of POP-1 by LIT-1 in C. elegans.
“The activation mechanism of β-catenin-TCF complex by NLK may be different from that of POP-1 by LIT-1 in C. elegans since NLK overexpression did not alter the nuclear localization of β-catenin or LEF1.”
Quote in the paperSubstantial claim - Premisecitation
In C. elegans, the phosphorylation sites in POP-1 by LIT-1 did not correspond to the target sites in LEF1 by NLK.
“In C. elegans, the phosphorylation sites in POP-1 by LIT-1 were identified and these sites did not correspond to the target sites in LEF1 by NLK.16)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] source
- Interpretationreasoning
The cell types in which NLK plays a suppressive role are epithelial origin (293 and DLD-1).
“One important aspect in this issue is that the cell types in which NLK plays a suppressive role are epithelial origin (293 and DLD-1).”
Quote in the paperSubstantial claim - Interpretationown data
NLK is a specific activator of β-catenin-TCF complex in osteosarcoma and neuroblastoma cells.
“Taken together, these results suggest that NLK is a specific activator of β-catenin-TCF complex in osteosarcoma and neuroblastoma cells.”
- Also stated in: § Discussion · boosted
“activation of the reporter gene expression by NLK is specific to the β-catenin-TCF complex in these cell lines”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Interpretationcitation
NLK and LEF1 act collaboratively in the same signaling pathway concerning B-cell proliferation.
“suggesting that both NLK and LEF1 act collaboratively in the same signaling pathway concerning B-cell proliferation.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationown data
NLK positively regulates Wnt/β-catenin signaling in a cell type dependent manner.
“Our results suggest that NLK positively regulates Wnt/β-catenin signaling in a cell type dependent manner through an unidentified mechanism.”
- Also stated in: § Introduction · hedged
“Our results suggest that NLK can be a positive regulator of the Wnt signaling pathway in certain mammalian cell types.”
Quote in the paperSubstantial claim- The authors state this as an assumption: NLK may play a positive role for Wnt signaling in mammalian cells.
- Also stated in: § Introduction · hedged
- Classified as probably not a substantial claim. 13
- May combine two claims. 3
Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).
PremisecitationDNA binding of LEF1 decreases with its phosphorylation at threonine 155 and serine 166 by overexpression of NLK.
“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)”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [17] source
- cites [34] source
The Results identify Thr-155 and Ser-166 as NLK phosphorylation sites in LEF-1 and show that NLK repression of LEF-1 reporter activity requires those sites. But the DNA-binding experiment in the Results tests the β-catenin–TCF-4 complex, not LEF-1; it therefore does not establish the claimed decrease in LEF-1 DNA binding. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTCF has a biphasic role in Wnt signaling: positive when signaling is activated and suppressive when signaling is suppressed.
“It is noteworthy that TCF has a biphasic role in Wnt signaling; it plays a positive role when the signaling is activated and a suppressive role when the signaling is suppressed.22), 23)”
Quote in the paperNot a substantial claim2 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNmo could be a suppressor of Wnt signaling.
“Subsequent Drosophila studies also indicated that Nmo could be a suppressor of Wnt signaling18)–20)”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [18] 18) Verheyen, E.M., Mirkovic, I., MacLean, S.J., Langmann, C., Andrews, B.C. and MacKinnon, C. (2001) Mech. Dev. <B>101</B>, 119-132.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [19] 19) Mirkovic, I., Charish, K., Gorski, S.M., McKnight, K. and Verheyen, E.M. (2002) Mech. Dev. <B>119</B>, 9-20. source
- cites [20] source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGenetic disruption of NLK causes severe lymphocyte reduction, especially of the B-cell lineage, in mice.
“In mice, genetic disruption of NLK caused severe lymphocyte reduction, especially of the B-cell lineage.28)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationZebrafish NLK is a positive regulator of Wnt signaling in ventrolateral mesoderm formation and patterning of the midbrain.
“Thorpe et al. revealed that zebrafish NLK appeared to be a positive regulator of Wnt signaling in ventrolateral mesoderm formation and patterning of the midbrain.26)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] source
Classified as probably not a substantial claim.
PremisecitationPOP-1 positively mediates Wnt signal in C. elegans.
“Korswagen et al. reported that POP-1 positively mediates Wnt signal in C. elegans.24)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenEach experiment was performed at least twice in triplicate.
“Each experiment was performed at least twice in triplicate.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe lit-1 gene is required for pop-1 function in worm gonadogenesis.
“Siegfried et al. showed that the lit-1 gene is required for pop-1 function in the worm gonadogenesis.25)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] SIEGFRIED K R, 2002 source
May combine two claims.
InterpretationreasoningThe effect of mammalian NLK on Wnt signaling depends on cell type: suppressive in 293 and DLD-1, positive in SaOS-2, NB39-nu, and Nh12.
“Thus, the effect of mammalian NLK on Wnt signaling seems to depend on the cell type; NLK plays some suppressive role in Wnt signaling in 29317) and DLD-1 cell lines30) and a positive role in SaOS-2, NB39-nu and Nh12 cell lines (the present study).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenLuciferase activity was normalized to that of lysate transfected with pcDNA3-MYC-β-catenin ΔN only as 1.
“The luciferase activity of each cell lysate was further normalized with that of the lysate transfected with pcDNA3-MYC-β-catenin ΔN only as 1 otherwise specified.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown datapFOPFLASH was used as a negative control reporter for pTOPFLASH with mutant TCF/LEF binding sites.
“Reporter gene analysis with pFOPFLASH, a negative control reporter for pTOPFLASH with mutant TCF/LEF binding sites, showed no activation”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe total amount of plasmid DNA per well was adjusted by adding pcDNA3.
“The total amount of plasmid DNA per well was adjusted by adding pcDNA3.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationGenetic disruption of LEF1 causes severe reduction of the B220+ cell lineage in mice.
“the genetic disruption of a TCF homolog, lymphoid enhancer factor 1 (LEF1), caused severe reduction of the B220+ cell lineage in mice,29)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNLK suppresses the transcriptional activity of the β-catenin-TCF complex through phosphorylation of TCF in human 293 cells.
“Ishitani et al. correspondingly reported that NLK could suppress the transcriptional activity of the β-catenin-TCF complex through phosphorylation of TCF in human 293 cells.17)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] source
The authors state this as an assumption.
Either β-catenin or TCF or both are the NLK substrates.
“It is reasonable to assume that either β-catenin or TCF or both should be the NLK substrates.”
The authors state this as an assumption.
NLK may play a positive role for Wnt signaling in mammalian cells.
“Considering the evolutional conservation of Wnt signaling pathways, it is reasonable to assume that NLK may play a positive role for Wnt signaling in mammalian cells.27)”
Cites
Wnt signalling in stem cells and cancer
Reya, T., & Clevers, H. (2005) · Nature · doi:10.1038/nature03319 · Cited by 3,666 · see citing works
β-Catenin regulates expression of cyclin D1 in colon carcinoma cells
Tetsu, O., & McCormick, F. (1999) · Nature · doi:10.1038/18884 · Cited by 3,601 · see citing works
The mitogen-activated protein kinase signal transduction pathway
Davis, R. J. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82362-6 · Cited by 2,112 · see citing works
Linking Colorectal Cancer to Wnt Signaling
Bienz, M., & Clevers, H. C. (2000) · Cell · doi:10.1016/s0092-8674(00)00122-7 · Cited by 1,516 · see citing works
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 · see citing works
Fearnhead, N. S. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.7.721 · Cited by 882 · see citing works
Wnt Signaling and an APC-Related Gene Specify Endoderm in Early C. elegans Embryos
Rocheleau, C. E., Downs, W. D., Lin, R., Wittmann, C., Bei, Y., Cha, Y.-H., Ali, M., Priess, J. R., & Mello, C. C. (1997) · Cell · doi:10.1016/s0092-8674(00)80531-0 · Cited by 660 · see citing works
The oncogenic activation of β-catenin
Polakis, P. G. (1999) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)80003-3 · Cited by 651 · see citing works
Ishitani, T., Ninomiya-Tsuji, J., Nagai, S.-I., Nishita, M., Meneghini, M., Barker, N., Waterman, M., Bowerman, B., Clevers, H., Shibuya, H., et al. (1999) · Nature · doi:10.1038/21674 · Cited by 624 · see citing works
Ishitani, T., Kishida, S., Hyodo‐Miura, J., Ueno, N., Yasuda, J., Waterman, M. L., Shibuyà, H., Moon, R. T., Ninomiya‐Tsuji, J., & Matsumoto, K. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.23.1.131-139.2003 · Cited by 540 · see citing works
Self-citationWnt Signaling Polarizes an Early C. elegans Blastomere to Distinguish Endoderm from Mesoderm
Thorpe, C. J., Schlesinger, A., Carter, J. C., & Bowerman, B. A. (1997) · Cell · doi:10.1016/s0092-8674(00)80530-9 · Cited by 514 · see citing works
Wnt Signaling Regulates B Lymphocyte Proliferation through a LEF-1 Dependent Mechanism
Reya, T., O'Riordan, M., Okamura, R., Devaney, E., Willert, K., Nusse, R., & Grosschedl, R. (2000) · Immunity · doi:10.1016/s1074-7613(00)00004-2 · Cited by 450 · see citing works
Rotation of photoreceptor clusters in the developing drosophila eye requires the nemo gene
Choi, K.-W., & Benzer, S. (1994) · Cell · doi:10.1016/0092-8674(94)90579-7 · Cited by 339 · see citing works
Lin, R., Thompson, S. L., & Priess, J. R. (1995) · Cell · doi:10.1016/0092-8674(95)90100-0 · Cited by 310 · see citing works
Meneghini, M. D., Ishitani, T., Carter, J. C., Hisamoto, N., Ninomiya-Tsuji, J., Thorpe, C. J., Hamill, D. R., Matsumoto, K., & Bowerman, B. (1999) · Nature · doi:10.1038/21666 · Cited by 293 · see citing works
POP-1 and Anterior–Posterior Fate Decisions in C. elegans Embryos
Lin, R., Hill, R. J., & Priess, J. R. (1998) · Cell · doi:10.1016/s0092-8674(00)80917-4 · Cited by 282 · see citing works
Rocheleau, C. E., Yasuda, J., Shin, T. H., Lin, R., Sawa, H., Okano, H., Priess, J. R., Davis, R. J., & Mello, C. C. (1999) · Cell · doi:10.1016/s0092-8674(00)80784-9 · Cited by 276 · see citing works
Self-citationDistinct β-catenins mediate adhesion and signalling functions in C. elegans
Korswagen, H. C., Herman, M. A., & Clevers, H. C. (2000) · Nature · doi:10.1038/35020099 · Cited by 218 · see citing works
Ishitani, T., Ninomiya-Tsuji, J., & Matsumoto, K. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.4.1379-1389.2003 · Cited by 212 · see citing works
Sawa, H., Lobel, L. I., & Horvitz, H. R. (1996) · Genes & Development · doi:10.1101/gad.10.17.2189 · Cited by 209 · see citing works
Binary specification of the embryonic lineage in Caenorhabditis elegans
Kaletta, T., Schnabel, H., & Schnabel, R. (1997) · Nature · doi:10.1038/36869 · Cited by 161 · see citing works
Kidd, A. R., Miskowski, J. A., Siegfried, K. R., Sawa, H., & Kimble, J. E. (2005) · Cell · doi:10.1016/j.cell.2005.03.029 · Cited by 144 · see citing works
Lo, M.-C., Gay, F., Odom, R., Shi, Y., & Lin, R. (2004) · Cell · doi:10.1016/s0092-8674(04)00203-x · Cited by 138 · see citing works
POP-1 controls axis formation during early gonadogenesis in<i>C. elegans</i>
Siegfried, K. R., & Kimble, J. (2002) · Development · doi:10.1242/dev.129.2.443 · Cited by 136 · see citing works
Nlk is a murine protein kinase related to Erk/MAP kinases and localized in the nucleus
Brott, B. K., Pinsky, B. A., & Erikson, R. L. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.3.963 · Cited by 130 · see citing works
Chromatin-specific regulation of LEF-1–β-catenin transcription activation and inhibition in vitro
Tutter, A. V., Fryer, C. J., & Jones, K. A. (2001) · Genes & Development · doi:10.1101/gad.946501 · Cited by 107 · see citing works
Lymphoid enhancer factor/T cell factor expression in colorectal cancer
Waterman, M. L. (2004) · Cancer and Metastasis Reviews · doi:10.1023/a:1025858928620 · Cited by 106 · see citing works
Maduro, M., Kasmir, J. J., Zhu, J., & Rothman, J. H. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.06.022 · Cited by 92 · see citing works
Thorpe, C. J., & Moon, R. T. (2004) · Development · doi:10.1242/dev.01171 · Cited by 84 · see citing works
Nemo is an inducible antagonist of Wingless signaling during<i>Drosophila</i>wing development
Zeng, Y. A., & Verheyen, E. M. (2004) · Development · doi:10.1242/dev.01177 · Cited by 60 · see citing works
Nemo-like kinase induces apoptosis in DLD-1 human colon cancer cells
Yasuda, J., Tsuchiya, A., Yamada, T., Sakamoto, M., Sekiya, T., & Hirohashi, S. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)01343-3 · Cited by 56 · see citing works
Self-citationFreeman, M., & Bienz, M. (2001) · EMBO Reports · doi:10.1093/embo-reports/kve019 · Cited by 52 · see citing works
Drosophila nemo is an essential gene involved in the regulation of programmed cell death
Mirkovic, I., Charish, K., Gorski, S. M., McKnight, K., & Verheyen, E. M. (2002) · Mechanisms of Development · doi:10.1016/s0925-4773(02)00289-7 · Cited by 51 · see citing works
The tissue polarity gene nemo carries out multiple roles in patterning during Drosophila development
Verheyen, E. M., Mirkovic, I., MacLean, S. J., Langmann, C., Andrews, B. C., & MacKinnon, C. (2001) · Mechanisms of Development · doi:10.1016/s0925-4773(00)00574-8 · Cited by 45 · see citing works
Nemo‐like kinase suppresses a wide range of transcription factors, including nuclear factor‐kB
Yasuda, J., Yokoo, H., Yamada, T., Kitabayashi, I., Sekiya, T., & Ichikawa, H. (2004) · Cancer Science · doi:10.1111/j.1349-7006.2004.tb03170.x · Cited by 45 · see citing works
Self-citationOnly one nemo-like kinase gene homologue in invertebrate and mammalian genomes
Kortenjann, M., Wehrle, C., Nehls, M. C., & Boehm, T. L. J. (2001) · Gene · doi:10.1016/s0378-1119(01)00710-7 · Cited by 8 · see citing works
Advocating Asymmetry and the POP-1 Paradox: Noncanonical Wnt Signaling in C. elegans
Bowerman, B. A. (2005) · Cell · doi:10.1016/j.cell.2005.05.020 · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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 · see citing works
Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase
Wilkes, M. C., Siva, K., Chen, J., Varetti, G., Youn, M., Chae, H.-D., Ek, F., Olsson, R., Lundbäck, T., Dever, D. P., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17100-z · Cited by 17 · see citing works
Wilkes, M. C., Jung, K., Lee, B. E., et al. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100988 · Cited by 14 · see citing works
Potential Regulatory Effects of miR-182-3p in Osteosarcoma via Targeting EBF2
Chen, G., Yu, W., Li, Z., Wang, Q., Yang, Q., Du, Z., Zhang, G., & Song, Y. (2019) · BioMed Research International · doi:10.1155/2019/4897905 · Cited by 13 · see citing works
Wilkes, M. C., Siva, K., Varetti, G., Mercado, J. D., Wentworth, E. P., Pérez, C. A., Saxena, M., Kam, S., Kapur, S., Chen, J., et al. (2020) · Experimental Hematology · doi:10.1016/j.exphem.2020.09.187 · Cited by 13 · see citing works
Construction of microRNA–messenger networks for human osteosarcoma
Ma, G., Zhang, C., Luo, W., et al. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28107 · Cited by 13 · see citing works
“NLK, which protein bears significant similarity to MAPKs in the kinase domain, is also related to the downstreamMAPK and osteosarcoma (Brott, Pinsky, & Erikson, 1998; Yasuda & Ichikawa, 2007).”
Background
- Authors
- YASUDA, J., & ICHIKAWA, H.
- Affiliations
- National Cancer Centre Japan (JP)
- Cancer Transcriptome Project, National Cancer Center Research Institute
- Venue
- Proceedings of the Japan Academy, Series B
- Publisher
- Japan Academy
- Published
- 2007
- Volume
- 83
- Issue
- 1
- Pages
- 16-25
- ISSN
- 0386-2208 (ISSN-L)
- 1349-2896
- PMC
- PMC3756733
- OpenAlex
- W2018925606
- Semantic Scholar
- 512ae8fba11ba4877042539831463f5ef37efb6c
- Cited by
- 6
- References
- 38
- Citations by year
- 2021: 1 · 2020: 2 · 2019: 2 · 2015: 1
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the Japan Academy Series B (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, 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, Wnt/β-catenin signaling, transcriptional activation, osteosarcoma, neuroblastoma, LEF1, kinase activity
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-18.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-18.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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