CoChat
Sign Up
Cited by 10Cardiac Fibrosis and RemodelingSignaling Pathways in DiseaseCongenital heart defects research

Nemo-Like Kinase (NLK) Is a Pathological Signaling Effector in the Mouse Heart

Open access
Liu, Ruijie, Khalil, Hadi, Lin, Suh-Chin J., Sargent, Michelle A., York, Allen J., Molkentin, Jeffery D.·2016·PLOS ONE
DOI 10.1371/journal.pone.0164897PMC PMC5072578
Open this paper in CoChat — free accountOpen PDF

Abstract

Nemo-like kinase (NLK) is an evolutionary conserved serine/threonine protein kinase implicated in development, proliferation and apoptosis regulation. Here we identified NLK as a gene product induced in the hearts of mice subjected to pressure overload or myocardial infarction injury, suggesting a potential regulatory role with pathological stimulation to this organ. To examine the potential functional consequences of increased NLK levels, cardiac-specific transgenic mice with inducible expression of this gene product were generated, as well as cardiac-specific Nlk gene-deleted mice. NLK transgenic mice demonstrated baseline cardiac hypertrophy, dilation, interstitial fibrosis, apoptosis and progression towards heart failure in response to two surgery-induced cardiac disease models. In contrast, cardiac-specific deletion of Nlk from the heart, achieved by crossing a Nlk-loxP allele containing mouse with either a mouse containing a β-myosin heavy chain promoter driven Cre transgene or a tamoxifen inducible α-myosin heavy chain promoter containing transgene driving a MerCreMer cDNA, protected the mice from cardiac dysfunction following pathological stimuli. Mechanistically, NLK interacted with multiple proteins including the transcription factor Stat1, which was significantly increased in the hearts of NLK transgenic mice. These results indicate that NLK is a pathological effector in the heart.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0164897

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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 cardiac tissue-specific transgenic knock-out model of NLK was protected from pathology associated with pressure overload and infarction injury.

    “Furthermore, the cardiac tissue-specific transgenic knock-out model of NLK was protected from pathology associated with pressure overload and infarction injury [38].”

    From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [38]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 34

  1. [1]Lorell BH, Carabello BA. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation. 2000; 102(4): 470– 9.. 10908222
  2. [2]Frey N, Katus HA, Olson EN, Hill JA. Hypertrophy of the heart: a new therapeutic target? Circulation. 2004; 109(13): 1580– 9. 10.1161/01.CIR.0000120390.68287.BB. 15066961 · DOI
  3. [3]Brott BK, Pinsky BA, Erikson RL. Nlk is a murine protein kinase related to Erk/MAP kinases and localized in the nucleus. Proc Natl Acad Sci U S A. 1998; 95(3): 963– 8. 9448268 PMC18639
  4. [4]Satoh K, Ohnishi J, Sato A, Takeyama M, Iemura S, Natsume T, et al Nemo-like kinase-myocyte enhancer factor 2A signaling regulates anterior formation in Xenopus development. Mol Cell Biol. 2007; 27(21): 7623– 30. 10.1128/MCB.01481-07 17785444 PMC2169051 · DOI
  5. [6]Ke H, Masoumi KC, Ahlqvist K, Seckl MJ, Rydell-Tormanen K, Massoumi R. Nemo-like kinase regulates the expression of vascular endothelial growth factor (VEGF) in alveolar epithelial cells. Sci Rep. 2016; 6: 23987 10.1038/srep23987 27035511 PMC4817507 · DOI · Paper page
  6. [7]Kortenjann M, Nehls M, Smith AJ, Carsetti R, Schuler J, Kohler G, et al Abnormal bone marrow stroma in mice deficient for nemo-like kinase, Nlk. Eur J Immunol. 2001; 31(12): 3580– 7. 10.1002/1521-4141(200112)31:12<3580::AID-IMMU3580>3.0.CO;2-N. 11745377 · DOI
  7. [8]Yasuda J, Tsuchiya A, Yamada T, Sakamoto M, Sekiya T, Hirohashi S. Nemo-like kinase induces apoptosis in DLD-1 human colon cancer cells. Biochem Biophys Res Commun. 2003; 308(2): 227– 33.. 12901858
  8. [9]Cheng X, Liang J, Teng Y, Fu J, Miao S, Zong S, et al Nemo-like kinase promotes etoposide-induced apoptosis of male germ cell-derived GC-1 cells in vitro. FEBS Lett. 2012; 586(10): 1497– 503. 10.1016/j.febslet.2012.04.005. 22673516 · DOI
  9. [10]Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J, Waterman M, et al The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling. Mol Cell Biol. 2003; 23(1): 131– 9. 10.1128/MCB.23.1.131-139.2003 12482967 PMC140665 · DOI
  10. [11]Kim S, Kim Y, Lee J, Chung J. Regulation of FOXO1 by TAK1-Nemo-like kinase pathway. J Biol Chem. 2010; 285(11): 8122– 9. 10.1074/jbc.M110.101824 20061393 PMC2832963 · DOI
  11. [12]Sanbe A, Gulick J, Hanks MC, Liang Q, Osinska H, Robbins J. Reengineering inducible cardiac-specific transgenesis with an attenuated myosin heavy chain promoter. Circ Res. 2003; 92(6): 609– 16. 10.1161/01.RES.0000065442.64694.9F. 12623879 · DOI
  12. [13]Purcell NH, Wilkins BJ, York A, Saba-El-Leil MK, Meloche S, Robbins J, et al Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc Natl Acad Sci U S A. 2007; 104(35): 14074– 9. 10.1073/pnas.0610906104 17709754 PMC1955824 · DOI
  13. [14]De Windt LJ, Lim HW, Haq S, Force T, Molkentin JD. Calcineurin promotes protein kinase C and c-Jun NH2-terminal kinase activation in the heart. Cross-talk between cardiac hypertrophic signaling pathways. J Biol Chem. 2000; 275(18): 13571– 9.. 10788473
  14. [15]Wilkins BJ, Dai YS, Bueno OF, Parsons SA, Xu J, Plank DM, et al Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res. 2004; 94(1): 110– 8. 10.1161/01.RES.0000109415.17511.18. 14656927 · DOI
  15. [16]Maillet M, Purcell NH, Sargent MA, York AJ, Bueno OF, Molkentin JD. DUSP6 (MKP3) null mice show enhanced ERK1/2 phosphorylation at baseline and increased myocyte proliferation in the heart affecting disease susceptibility. J Biol Chem. 2008; 283(45): 31246– 55. 10.1074/jbc.M806085200 18753132 PMC2576531 · DOI
  16. [17]Kaiser RA, Liang Q, Bueno O, Huang Y, Lackey T, Klevitsky R, et al Genetic inhibition or activation of JNK1/2 protects the myocardium from ischemia-reperfusion-induced cell death in vivo. J Biol Chem. 2005; 280(38): 32602– 8. 10.1074/jbc.M500684200. 16043490 · DOI
  17. [18]Dimauro I, Pearson T, Caporossi D, Jackson MJ. A simple protocol for the subcellular fractionation of skeletal muscle cells and tissue. BMC Res Notes. 2012; 5: 513 10.1186/1756-0500-5-513 22994964 PMC3508861 · DOI
  18. [19]Mirkovic I, Charish K, Gorski SM, McKnight K, Verheyen EM. Drosophila nemo is an essential gene involved in the regulation of programmed cell death. Mech Dev. 2002; 119(1): 9– 20.. 12385750
  19. [20]Braid LR, Verheyen EM. Drosophila nemo promotes eye specification directed by the retinal determination gene network. Genetics. 2008; 180(1): 283– 99. 10.1534/genetics.108.092155 18757943 PMC2535682 · DOI
  20. [21]Shaw-Hallgren G, Chmielarska Masoumi K, Zarrizi R, Hellman U, Karlsson P, Helou K, et al Association of nuclear-localized Nemo-like kinase with heat-shock protein 27 inhibits apoptosis in human breast cancer cells. PLoS One. 2014; 9(5): e96506 10.1371/journal.pone.0096506 24816797 PMC4015990 · DOI · Paper page
  21. [22]Ishitani T, Ishitani S. Nemo-like kinase, a multifaceted cell signaling regulator. Cell Signal. 2013; 25(1): 190– 7. 10.1016/j.cellsig.2012.09.017. 23000342 · DOI · Paper page
  22. [23]Emami KH, Brown LG, Pitts TE, Sun X, Vessella RL, Corey E. Nemo-like kinase induces apoptosis and inhibits androgen receptor signaling in prostate cancer cells. Prostate. 2009; 69(14): 1481– 92. 10.1002/pros.20998 19514049 PMC2908180 · DOI
  23. [24]Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007; 178(5): 2623– 9.. 17312100
  24. [25]O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015; 66: 311– 28. 10.1146/annurev-med-051113-024537. 25587654 PMC5634336 · DOI
  25. [26]McCormick J, Suleman N, Scarabelli TM, Knight RA, Latchman DS, Stephanou A. STAT1 deficiency in the heart protects against myocardial infarction by enhancing autophagy. J Cell Mol Med. 2012; 16(2): 386– 93. 10.1111/j.1582-4934.2011.01323.x 21447043 PMC3823301 · DOI
  26. [27]Jacoby JJ, Kalinowski A, Liu MG, Zhang SS, Gao Q, Chai GX, et al Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc Natl Acad Sci U S A. 2003; 100(22): 12929– 34. 10.1073/pnas.2134694100 14566054 PMC240721 · DOI · Paper page
  27. [28]Ishitani S, Inaba K, Matsumoto K, Ishitani T. Homodimerization of Nemo-like kinase is essential for activation and nuclear localization. Mol Biol Cell. 2011; 22(2): 266– 77. 10.1091/mbc.E10-07-0605 21118996 PMC3020921 · DOI
  28. [29]Ota S, Ishitani S, Shimizu N, Matsumoto K, Itoh M, Ishitani T. NLK positively regulates Wnt/beta-catenin signalling by phosphorylating LEF1 in neural progenitor cells. EMBO J. 2012; 31(8): 1904– 15. 10.1038/emboj.2012.46 22373574 PMC3343332 · DOI · Paper page
  29. [30]Kanei-Ishii C, Ninomiya-Tsuji J, Tanikawa J, Nomura T, Ishitani T, Kishida S, et al Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK. Genes Dev. 2004; 18(7): 816– 29. 10.1101/gad.1170604 15082531 PMC387421 · DOI
  30. [31]Wu L, Archacki SR, Zhang T, Wang QK. Induction of high STAT1 expression in transgenic mice with LQTS and heart failure. Biochem Biophys Res Commun. 2007; 358(2): 449– 54. 10.1016/j.bbrc.2007.04.119 17490620 PMC3505674 · DOI
  31. [32]Stephanou A, Latchman DS. STAT-1: a novel regulator of apoptosis. Int J Exp Pathol. 2003; 84(6): 239– 44. 10.1111/j.0959-9673.2003.00363.x 14748743 PMC2517573 · DOI
  32. [33]Battle TE, Frank DA. The role of STATs in apoptosis. Curr Mol Med. 2002; 2(4): 381– 92.. 12108949
  33. [34]Wan CK, Andraski AB, Spolski R, Li P, Kazemian M, Oh J, et al Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells. Proc Natl Acad Sci U S A. 2015; 112(30): 9394– 9. 10.1073/pnas.1511711112 26170288 PMC4522759 · DOI
  34. [35]Stephanou A, Brar BK, Scarabelli TM, Jonassen AK, Yellon DM, Marber MS, et al Ischemia-induced STAT-1 expression and activation play a critical role in cardiomyocyte apoptosis. J Biol Chem. 2000; 275(14): 10002– 8.. 10744676

Cited by

Sorted by citations

Authors
Liu, R., Khalil, H., Lin, S.-C. J., Sargent, M. A., York, A. J., & Molkentin, J. D.
Affiliations
Cincinnati Children's Hospital Medical Center (US)
Corresponding author
Molkentin, Jeffery D.
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2016-10-20
Volume
11
Issue
10
Pages
e0164897
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0164897
PMC
PMC5072578
OpenAlex
W2536088360
Cited by
10
References
1
Citations by year
2026: 3 · 2025: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 2
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ScholarWorks - GVSU (Grand Valley State University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Howard Hughes Medical Institute (Investigatorship)
  • National Heart, Lung, and Blood Institute (R37HL60562, T32HL125204)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
Keywords
Nemo-like kinase, cardiac hypertrophy, heart failure, myocardial infarction, pressure overload, myocardial fibrosis, cardiomyocyte apoptosis, STAT1, cardiac-specific transgenic mice
MeSH terms
Animals, Cells, Cultured, Echocardiography, Female, Heart, Humans, Male, Mice, Transgenic, Cardiomyopathies, Myocardium, Promoter Regions, Genetic, Protein Binding, Signal Transduction, Rats, Sprague-Dawley, Protein Serine-Threonine Kinases, Myosin Heavy Chains, Mitogen-Activated Protein Kinases, Myocytes, Cardiac, STAT1 Transcription Factor, Mice, Rats, HEK293 Cells

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.

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 ›

Are you an author, or do you see a problem with this page? Request a review