The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1
Open accessAbstract
We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP-activated protein kinase (AMPK). A total of 12 human kinases (NUAK1, NUAK2, BRSK1, BRSK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) are related to AMPK. Here we demonstrate that LKB1 can phosphorylate the T-loop of all the members of this subfamily, apart from MELK, increasing their activity >50-fold. LKB1 catalytic activity and the presence of MO25 and STRAD are required for activation. Mutation of the T-loop Thr phosphorylated by LKB1 to Ala prevented activation, while mutation to glutamate produced active forms of many of the AMPK-related kinases. Activities of endogenous NUAK2, QIK, QSK, SIK, MARK1, MARK2/3 and MARK4 were markedly reduced in LKB1-deficient cells. Neither LKB1 activity nor that of AMPK-related kinases was stimulated by phenformin or AICAR, which activate AMPK. Our results show that LKB1 functions as a master upstream protein kinase, regulating AMPK-related kinases as well as AMPK. Between them, these kinases may mediate the physiological effects of LKB1, including its tumour suppressor function.
Overview
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.
Integrity signals
Registry
Cites
Statistics
Verification
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.
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 check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“LKB-1 phosphorylates and activates PAR-1 (120,122,123), but also phosphorylates the inactivating Ser-9 on GSK-3β and may be the elusive GSK-3β kinase activated by Wnt signaling (124).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [122]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The protein kinase complement of the human genome
Manning, G., Whyte, D. B., Martinez, R., Hunter, T., & Sudarsanam, S. (2002) · Science · doi:10.1126/science.1075762 · Cited by 8,145
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652
Hawley, S. A., Boudeau, J., Reid, J. L., Mustard, K. J., Udd, L., Mäkelä, T. P., Alessi, D. R., & Hardie, D. G. (2003) · Journal of Biology · doi:10.1186/1475-4924-2-28 · Cited by 1,694
Self-citationA serine/threonine kinase gene defective in Peutz–Jeghers syndrome
Hemminki, A., Markie, D., Tomlinson, I. P. M., Avizienyte, E., Roth, S., Loukola, A., Bignell, G. R., Warren, W., Aminoff, M., Höglund, P., et al. (1998) · Nature · doi:10.1038/34432 · Cited by 1,680
LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
Woods, A., Johnstone, S. R., Dickerson, K., Leiper, F. C., Fryer, L. G. D., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M., & Carling, D. (2003) · Current Biology · doi:10.1016/j.cub.2003.10.031 · Cited by 1,650
Corton, J. M., Gillespie, J. G., Hawley, S. A., & Hardie, D. G. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.tb20498.x · Cited by 1,232
Self-citationPeutz-Jeghers syndrome is caused by mutations in a novel serine threoninekinase
Jenne, D. E., Reomann, H., Nezu, J., Friedel, W., Loff, S., Jeschke, R., Müller, O., Back, W. E., & Zimmer, M. (1998) · Nature Genetics · doi:10.1038/ng0198-38 · Cited by 1,201
Guo, S., & Kemphues, K. J. (1995) · Cell · doi:10.1016/0092-8674(95)90082-9 · Cited by 1,113
Fryer, L. G. D., Patel, A. P., & Carling, D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202489200 · Cited by 1,035
Drewes, G., Ebneth, A., Preuss, U., Mandelkow, E.-M., & Mandelkow, E. (1997) · Cell · doi:10.1016/s0092-8674(00)80208-1 · Cited by 878
Management of cellular energy by the AMP‐activated protein kinase system
Hardie, D. G., Scott, J. W., Pan, D. A., & Hudson, E. R. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00560-x · Cited by 868
Self-citationIdentification of genes required for cytoplasmic localization in early C. elegans embryos
Kemphues, K. J., Priess, J. R., Morton, D. G., & Cheng, N. N. (1988) · Cell · doi:10.1016/s0092-8674(88)80024-2 · Cited by 859
Hawley, S. A., Gadalla, A. E., Olsen, G. S., & Hardie, D. G. (2002) · Diabetes · doi:10.2337/diabetes.51.8.2420 · Cited by 696
Self-citationActivation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases
Hong, S. P., Leiper, F. C., Woods, A., Carling, D., & Carlson, M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1533136100 · Cited by 617
Boudeau, J., Baas, A. F., Deák, M., MORRICE, N. A., Kieloch, A., Schutkowski, M., Prescott, A. R., Clevers, H. C., & Alessi, D. R. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg490 · Cited by 456
Self-citationDAVIES, S. P., Carling, D., & Hardie, D. G. (1989) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1989.tb15185.x · Cited by 431
Self-citationActivation of the tumour suppressor kinase LKB1 by the STE20‐like pseudokinase STRAD
Baas, A. F., Boudeau, J., Sapkota, G. P., Smit, L., Medema, R. H., Morrice, N. A., Alessi, D. R., & Clevers, H. C. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg292 · Cited by 385
Self-citationDale, S. J., Wilson, W. A., Edelman, A. M., & Hardie, D. G. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)00172-6 · Cited by 324
Self-citationGrowth suppression by Lkb1 is mediated by a G 1 cell cycle arrest
Tiainen, M., Ylikorkala, A., & Mäkelä, T. P. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.16.9248 · Cited by 302
Self-citationA role for Drosophila LKB1 in anterior–posterior axis formation and epithelial polarity
Martin, S. G., & Johnston, D. S. (2003) · Nature · doi:10.1038/nature01296 · Cited by 293
Shulman, J. M., Benton, R., & Johnston, D. S. (2000) · Cell · doi:10.1016/s0092-8674(00)80848-x · Cited by 288
Elm1p Is One of Three Upstream Kinases for the Saccharomyces cerevisiae SNF1 Complex
Sutherland, C. M., Hawley, S. A., McCartney, R. R., Leech, A., Stark, M. J. R., Schmidt, M. C., & Hardie, D. G. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00459-7 · Cited by 283
Self-citationWatts, J. L., Morton, D. G., Bestman, J. E., & Kemphues, K. J. (2000) · Development · doi:10.1242/dev.127.7.1467 · Cited by 242
Woods, A., Vertommen, D., Neumann, D., Tuerk, R. D., Bayliss, J., Schlattner, U., Wallimann, T., Carling, D., & Rider, M. H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303946200 · Cited by 242
Jakobsen, S. N., Hardie, D. G., Morrice, N., & Tornqvist, H. E. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.c100483200 · Cited by 238 · cited 2×
“equivalent to Ser789 in rat IRS1, shown to be phosphorylated by AMPK ( Jakobsen et al, 2001 ).”
BackgroundSelf-citationC-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding.
Peng, C. Y., Graves, P. R., Ogg, S., Thoma, R. S., Byrnes, M. J., Wu, Z., Stephenson, M. T., & Piwnica-Worms, H. M. (1998) · PubMed · Cited by 223
Growth arrest by the LKB1 tumor suppressor: induction of p21WAF1/CIP1
Tiainen, M. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.13.1497 · Cited by 200
MARKK, a Ste20‐like kinase, activates the polarity‐inducing kinase MARK/PAR‐1
Timm, T., Li, X., Biernat, J., Jiao, J., Mandelkow, E., Vandekerckhove, J., & Mandelkow, E. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg447 · Cited by 198
Brajenovic, M., Joberty, G., Küster, B., Bouwmeester, T., & Drewes, G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312171200 · Cited by 193
LKB1, a protein kinase regulating cell proliferation and polarity
Boudeau, J., Sapkota, G. P., & Alessi, D. R. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00642-2 · Cited by 189
Self-citationSteinman, R. A., Hoffman‐Liebermann, B., Liebermann, D. A., & Fisher, P. B. (1995) · Science · doi:10.1126/science.7716532 · Cited by 186
Cloning of a novel kinase (SIK) of the SNF1/AMPK family from high salt diet‐treated rat adrenal1
Wang, Z.-N., Takemori, H., Halder, S. K., Nonaka, Y., & Okamoto, M. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00708-5 · Cited by 161
Identification of a Novel Protein Kinase Mediating Akt Survival Signaling to the ATM Protein
Suzuki, A., Kusakai, G.-I., Kishimoto, A., Lu, J., Ogura, T., Lavin, M. F., & Esumi, H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206025200 · Cited by 161
Horike, N., Takemori, H., Katoh, Y., Doi, J., Min, L., Asano, T., Sun, X. J., Yamamoto, H., Kasayama, S., Muraoka, M., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211770200 · Cited by 161
Yeast Pak1 Kinase Associates with and Activates Snf1
Nath, N., McCartney, R. R., & Schmidt, M. C. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.11.3909-3917.2003 · Cited by 149
LKB1 (XEEK1) regulates Wnt signalling in vertebrate development
Ossipova, O., Bardeesy, N. M., DePinho, R. A., & Green, J. B. A. (2003) · Nature Cell Biology · doi:10.1038/ncb1048 · Cited by 134
Discovery of PDKI, One of the Missing Links in Insulin Signal Transduction
Alessi, D. R. (2001) · Biochemical Society Transactions · doi:10.1042/bst0290001 · Cited by 128
Self-citationSapkota, G. P., Deák, M., Kieloch, A., MORRICE, N. A., Goodarzi, A. A., Smythe, C., Shiloh, Y., Lees‐Miller, S. P., & Alessi, D. R. (2002) · Biochemical Journal · doi:10.1042/bj20021284 · Cited by 123
Self-citation[A serine/threonine kinase gene defective in Peutz-Jeghers syndrome].
Hemminki, A., Avizienyte, E., Roth, S., Loukola, A., Aaltonen, L. A., Järvinen, H., & de la Chapelle, A. (1998) · PubMed · Cited by 116
Morton, D. G., Roos, J. M., & Kemphues, K. J. (1992) · Genetics · doi:10.1093/genetics/130.4.771 · Cited by 108
Regulation of the Wnt signalling component PAR1A by the Peutz–Jeghers syndrome kinase LKB1
Spicer, J. F., Rayter, S., Young, N., Elliott, R. J. R., Ashworth, A., & Smith, D. P. (2003) · Oncogene · doi:10.1038/sj.onc.1206669 · Cited by 104
Vulsteke, V., Beullens, M., Boudrez, A., Keppens, S., Eynde, A. V., Rider, M. H., Stalmans, W., & Bollen, M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311466200 · Cited by 104
Suzuki, A., Kusakai, G.-I., Kishimoto, A., Lu, J., Ogura, T., & Esumi, H. (2003) · Oncogene · doi:10.1038/sj.onc.1206899 · Cited by 98
Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability
Boudeau, J., Deák, M., Lawlor, M. A., MORRICE, N. A., & Alessi, D. R. (2003) · Biochemical Journal · doi:10.1042/bj20021813 · Cited by 87
Self-citationDiscovery of PDK1, One of the Missing Links in Insulin Signal Transduction
Alessi, D. R. (2001) · Biochemical Society Transactions · doi:10.1042/0300-5127:0290001 · Cited by 82
Self-citationLefebvre, D. L., Bai, Y., Shahmolky, N., SHARMA, M., Poon, R. W. M., Drucker, D. J., & Rosen, C. F. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3550297 · Cited by 76
The Salt‐Inducible Kinase, SIK, Is Induced by Depolarization in Brain
Feldman, J. D., Vician, L. J., Crispino, M., Hoe, W., Baudry, M., & Herschman, H. R. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0742227.x · Cited by 71
Crystal structure of MO25α in complex with the C terminus of the pseudo kinase STE20-related adaptor
Milburn, C. C., Boudeau, J., Deák, M., Alessi, D. R., & van Aalten, D. M. F. (2004) · Nature Structural & Molecular Biology · doi:10.1038/nsmb716 · Cited by 67
Self-citationSchaefer, J. J., Oliver, G. C., & Henry, J. J. (1999) · Developmental Dynamics · doi:10.1002/(sici)1097-0177(199908)215:4 · Cited by 59
Buchet-Poyau, K., Mehenni, H., Radhakrishna, U., & Antonarakis, S. E. (2002) · Cytogenetic and Genome Research · doi:10.1159/000066620 · Cited by 52
Drewes, G., & Nurse, P. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)01080-9 · Cited by 47
A non-radioactive method for the assay of many serine/threonine-specific protein kinases
Ross, H., Armstrong, C. G., & Cohen, P. (2002) · Biochemical Journal · doi:10.1042/bj20020786 · Cited by 35
Salt-inducible kinase-mediated regulation of steroidogenesis at the early stage of ACTH-stimulation
Takemori, H., Doi, J., Horike, N., Katoh, Y., Li, M., Lin, X., Wang, Z.-N., Muraoka, M., & Okamoto, M. (2003) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/s0960-0760(03)00199-7 · Cited by 16
Cited by
Sorted by citations
The AMPK signalling pathway coordinates cell growth, autophagy and metabolism
Mihaylova, M. M., & Shaw, R. J. (2011) · Nature Cell Biology · doi:10.1038/ncb2329 · Cited by 2,923
Kahn, B. B., Alquier, T., Carling, D., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.12.003 · Cited by 2,799
Self-citationRoux, P. P., & Blenis, J. (2004) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.68.2.320-344.2004 · Cited by 2,540
Metformin and reduced risk of cancer in diabetic patients
Evans, J. M. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R., & Morris, A. D. (2005) · BMJ · doi:10.1136/bmj.38415.708634.f7 · Cited by 2,388
Self-citationAMP-activated/SNF1 protein kinases: conserved guardians of cellular energy
Hardie, D. G. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2249 · Cited by 2,261
Self-citation
Metadata
- Authors
- Lizcano, J. M., Göransson, O., Toth, R., Deak, M., Morrice, N. A., Boudeau, J., Hawley, S. A., Udd, L., Mäkelä, T. P., Hardie, D. G., & Alessi, D. R.
- Affiliations
- University of Dundee (GB)
- University of Helsinki (FI)
- Corresponding author
- Alessi, Dario R
- Venue
- The EMBO Journal
- Published
- 2004-02-19
- Volume
- 23
- Issue
- 4
- Pages
- 833-843
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC381014
- OpenAlex
- W2138319716
- Cited by
- 1,381
- References
- 53
- Citations by year
- 2026: 41 · 2025: 44 · 2024: 57 · 2023: 38 · 2022: 56 · 2021: 70 · 2020: 60 · 2019: 51 · 2018: 52 · 2017: 56 · 2016: 61 · 2015: 68 · 2014: 91 · 2013: 82 · 2012: 88
- FWCI
- 23.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- University of Dundee
- Merck KGaA
- Wellcome Trust (01488, QLG1-CT-2001-01488)
- Diabetes UK
- European Commission
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- LKB1, AMPK-related kinases, kinase activation, T-loop phosphorylation, STRAD, MO25, MARK kinases, MELK
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Amino Acid Sequence, Cell Line, Enzyme Activation, Fibroblasts, Humans, Molecular Sequence Data, Multienzyme Complexes, Mutation, Peptides, Phosphorylation, Protein Binding, Substrate Specificity, Protein Serine-Threonine Kinases, Protein Subunits, Adaptor Proteins, Vesicular Transport, AMP-Activated Protein Kinases
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
