Nlk is a murine protein kinase related to Erk/MAP kinases and localized in the nucleus
Open accessAbstract
Extracellular-signal regulated kinases/microtubule-associated protein kinases (Erk/MAPKs) and cyclin-directed kinases (Cdks) are key regulators of many aspects of cell growth and division, as well as apoptosis. We have cloned a kinase, Nlk , that is a murine homolog of the Drosophila nemo ( nmo ) gene. The Nlk amino acid sequence is 54.5% similar and 41.7% identical to murine Erk-2, and 49.6% similar and 38.4% identical to human Cdc2. It possesses an extended amino-terminal domain that is very rich in glutamine, alanine, proline, and histidine. This region bears similarity to repetitive regions found in many transcription factors. Nlk is expressed as a 4.0-kb transcript at high levels in adult mouse brain tissue, with low levels in other tissues examined, including lung, where two smaller transcripts of 1.0 and 1.5 kb are expressed as well. A 4.0-kb Nlk message is also present during embryogenesis, detectable at day E 10.5 , reaching maximal steady state levels at day E 12.5 , and then decreasing. Nlk transiently expressed in COS7 cells is a 60-kDa kinase detectable by its ability to autophosphorylate. Mutation of the ATP-binding Lys-155 to methionine abolishes its ability to autophosphorylate, as does mutation of a putative activating threonine in kinase domain VIII, to valine, aspartic, or glutamic acid. Subcellular fractionation indicates that 60–70% of Nlk is localized to the nucleus, whereas 30–40% of Nlk is cytoplasmic. Immunofluorescence microscopy confirms that Nlk resides predominantly in the nucleus. Nlk and Nmo may be the first members of a family of kinases with homology to both Erk/MAPKs and Cdks.
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NLK has an extended amino-terminal domain consisting of histidine, proline, alanine and glutamine.
“NLK also has an extended amino-terminal domain consisting of histidine, proline, alanine and glutamine [15].”
From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [15]
The Isolation and Characterization of the Nlk cDNA section describes an extended amino-terminal region extremely rich in histidine, proline, glutamine, and alanine. It says these four amino acids account for more than 70% of the region, not that the region consists solely of them. (LLM, conf=0.84)
Experimental — accuracy not yet measuredNLK is a MAPK-like kinase and targets the (S/T-P) consensus motif for phosphorylation.
“since it is a MAPK-like kinase (Brott et al., 1998) and therefore targets the (S/T-P) consensus motif for phosphorylation.”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Brott et al., 1998
In “Isolation and Characterization of the Nlk cDNA” and the Discussion (page numbers not supplied), the paper describes Nlk as related to Erk/MAP kinases. It says Nlk may have proline-directed substrate specificity, but does not establish that it targets the (S/T-P) motif; the citing sentence states that inference as fact. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNLK is an evolutionarily conserved serine/threonine protein kinase.
“NLK is an evolutionarily conserved serine/threonine protein kinase (Choi and Benzer, 1994; Banfi et al., 1996; Brott et al., 1998; Meneghini et al., 1999).”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Brott et al., 1998
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Cites
The retinoblastoma protein and cell cycle control
Weinberg, R. A. (1995) · Cell · doi:10.1016/0092-8674(95)90385-2 · Cited by 4,862 · 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
Flagged first, then by citations
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Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases
Cargnello, M., & Roux, P. P. (2011) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00031-10 · Cited by 3,274 · 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
Atypical mitogen-activated protein kinases: Structure, regulation and functions
Coulombe, P., & Meloche, S. (2007) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.11.001 · Cited by 298 · see citing works
Röttinger, E., Croce, J., Lhomond, G., Besnardeau, L., Gache, C., & Lepage, T. (2006) · Development · doi:10.1242/dev.02603 · Cited by 54 · see citing works
Nemo‐like kinase is involved in NGF‐induced neurite outgrowth via phosphorylating MAP1B and paxillin
Ishitani, T., Ishitani, S., Matsumoto, K., & Itoh, M. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06400.x · Cited by 44 · see citing works
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 · see citing works
“If this is the case, then NLK will phosphorylate ATXN1 at serine (S) or threonine (T) residues followed by proline (P) because it is an MAPK-like kinase (Brott et al., 1998) and therefore targets the (S/T-P) consensus motif for phosphorylation.”
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 · see citing works
“NLK also has an extended amino-terminal domain consisting of histidine, proline, alanine and glutamine [15].”
BackgroundYASUDA, J., & ICHIKAWA, H. (2007) · Proceedings of the Japan Academy, Series B · doi:10.2183/pjab.83.16 · Cited by 6 · see citing works
Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS
Bekier, M. E., Pinarbasi, E., Krishnan, G., Mesojedec, J. J., Hurley, M., Harikumar Sheela, H., Collins, C. A., Ghaffari, L., de Majo, M., Ullian, E. M., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci188138 · Cited by 2 · see citing works
“…(KN) mutant of NLK, which harbors a point mutation in the kinase domain (K155M) that abrogates its enzymatic activity, as confirmed by loss of autophosphorylation (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/ JCI188138DS1) (20).”
Influential
- Authors
- Brott, B. K., Pinsky, B. A., & Erikson, R. L.
- Affiliations
- Harvard University (US)
- ORCID
- Pinsky, Benjamin A.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1998-02-03
- Volume
- 95
- Issue
- 3
- Pages
- 963-968
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC18639
- OpenAlex
- W2120865645
- Cited by
- 130
- References
- 2
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 5 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 2 · 2016: 6 · 2015: 5 · 2014: 8 · 2013: 8 · 2012: 5
- FWCI
- 2.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r35ca042580-14)
- National Cancer Institute (CA 42580)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- cyclin-dependent kinases, nuclear localization, autophosphorylation, kinase domain, embryonic gene expression, brain expression
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Brain, Cell Nucleus, Cloning, Molecular, Humans, Mice, Inbred BALB C, Microscopy, Fluorescence, Molecular Sequence Data, Molecular Weight, Phosphorylation, Blotting, Northern, Polymerase Chain Reaction, CDC2 Protein Kinase, Sequence Alignment, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, COS Cells, Mitogen-Activated Protein Kinases, Intracellular Signaling Peptides and Proteins, Mice
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