The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.
LKB1-Dependent Signaling Pathways
Abstract
This review focuses on remarkable recent findings concerning the mechanism by which the LKB1 protein kinase that is mutated in Peutz-Jeghers cancer syndrome operates as a tumor suppressor. We discuss evidence that the cellular localization and activity of LKB1 is controlled through its interaction with a catalytically inactive protein resembling a protein kinase, termed STRAD, and an armadillo repeat-containing protein, named mouse protein 25 (MO25). The data suggest that LKB1 functions as a tumor suppressor by not only inhibiting proliferation, but also by exerting profound effects on cell polarity and, most unexpectedly, on the ability of a cell to detect and respond to low cellular energy levels. Genetic and biochemical findings indicate that LKB1 exerts its effects by phosphorylating and activating 14 protein kinases, all related to the AMP-activated protein kinase. The work described in this review shows how a study of an obscure cancer syndrome can uncover new and important regulatory pathways, relevant to the understanding of multiple human diseases.
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Cites
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
The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin
Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S.-H., Bardeesy, N., DePinho, R. A., Montminy, M., & Cantley, L. C. (2005) · Science · doi:10.1126/science.1120781 · Cited by 1,950
Shaw, R. J., Kosmatka, M., Bardeesy, N., Hurley, R. L., Witters, L. A., DePinho, R. A., & Cantley, L. C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308061100 · Cited by 1,797
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
Hawley, S. A., Pan, D. A., Mustard, K. J., Ross, L., Bain, J., Edelman, A. M., Frenguelli, B. G., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.009 · Cited by 1,589
Recognition of Unique Carboxyl-Terminal Motifs by Distinct PDZ Domains
Songyang, Z., Fanning, A. S., Fu, C., Xu, J., Marfatia, S. M., Chishti, A. H., Crompton, A., Chan, A. C., Anderson, J. M., & Cantley, L. C. (1997) · Science · doi:10.1126/science.275.5296.73 · Cited by 1,385
LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1
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., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600110 · Cited by 1,381
Self-citationDrewes, G., Ebneth, A., Preuss, U., Mandelkow, E.-M., & Mandelkow, E. (1997) · Cell · doi:10.1016/s0092-8674(00)80208-1 · Cited by 878
Scott, J. W., Hawley, S. A., Green, K. A., Anis, M., Stewart, G., Scullion, G. A., Norman, D. G., & Hardie, D. G. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19874 · Cited by 754
Sakamoto, K., Göransson, O., Hardie, D. G., & Alessi, D. R. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00074.2004 · Cited by 299
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Mihaylova, M. M., & Shaw, R. J. (2011) · Nature Cell Biology · doi:10.1038/ncb2329 · Cited by 2,923
The LKB1-AMPK pathway: metabolism and growth control in tumour suppression
Shackelford, D. B., & Shaw, R. J. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2676 · Cited by 1,943
Metabolism of Inflammation Limited by AMPK and Pseudo-Starvation
O'Neill, L. A. J., & Hardie, D. G. (2013) · Nature · doi:10.1038/nature11862 · Cited by 1,133
New Users of Metformin Are at Low Risk of Incident Cancer
Libby, G., Donnelly, L. A., Donnan, P. T., Alessi, D. R., Morris, A. D., & Evans, J. M. M. (2009) · Diabetes Care · doi:10.2337/dc08-2175 · Cited by 996
Self-citationMetformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis
DeCensi, A., Puntoni, M., Goodwin, P., Cazzaniga, M., Gennari, A., Bonanni, B., & Gandini, S. (2010) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-10-0157 · Cited by 918
AMPK and SIRT1: a long-standing partnership?
Ruderman, N. B., Julia Xu, X., Nelson, L., Cacicedo, J. M., Saha, A. K., Lan, F., & Ido, Y. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00745.2009 · Cited by 903
SIRT1 Modulation of the Acetylation Status, Cytosolic Localization, and Activity of LKB1
Lan, F., Cacicedo, J. M., Ruderman, N., & Ido, Y. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805711200 · Cited by 825
AMPK activators: mechanisms of action and physiological activities
Kim, J., Yang, G., Kim, Y., Kim, J., & Ha, J. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.16 · Cited by 817
AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control
González, A., Hall, M. N., Lin, S.-C., & Hardie, D. G. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.01.015 · Cited by 797
SIRT1 Regulates Hepatocyte Lipid Metabolism through Activating AMP-activated Protein Kinase
Hou, X., Xu, S., Maitland-Toolan, K. A., Sato, K., Jiang, B., Ido, Y., Lan, F., Walsh, K., Wierzbicki, M., Verbeuren, T. J., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802187200 · Cited by 778
ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS
Alexander, A., Cai, S.-L., Kim, J., Nanez, A., Sahin, M., MacLean, K. H., Inoki, K., Guan, K.-L., Shen, J., Person, M. D., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913860107 · Cited by 717
Update on the treatment of type 2 diabetes mellitus
Marín-Peñalver, J. J., Martín-Timón, I., Sevillano-Collantes, C., & Cañizo-Gómez, F. J. D. (2016) · World Journal of Diabetes · doi:10.4239/wjd.v7.i17.354 · Cited by 647
Metabolic switching and fuel choice during T‐cell differentiation and memory development
van der Windt, G. J. W., & Pearce, E. L. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01150.x · Cited by 563
Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells
Nakada, D., Saunders, T. L., & Morrison, S. J. (2010) · Nature · doi:10.1038/nature09571 · Cited by 524
Molecular mechanism of action of metformin: old or new insights?
Rena, G., Pearson, E. R., & Sakamoto, K. (2013) · Diabetologia · doi:10.1007/s00125-013-2991-0 · Cited by 479
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Cantó, C., & Auwerx, J. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0454-z · Cited by 421
Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice
Huang, X., Wullschleger, S., Shpiro, N., McGuire, V. A., Sakamoto, K., Woods, Y. L., Mcburnie, W., Fleming, S., & Alessi, D. R. (2008) · Biochemical Journal · doi:10.1042/bj20080557 · Cited by 396
Self-citationMairet-Coello, G., Courchet, J., Pieraut, S., Courchet, V., Maximov, A., & Polleux, F. (2013) · Neuron · doi:10.1016/j.neuron.2013.02.003 · Cited by 351
Zu, Y., Liu, L., Lee, M. Y. K., Xu, C., Liang, Y., Man, R. Y., Vanhoutte, P. M., & Wang, Y. (2010) · Circulation Research · doi:10.1161/circresaha.109.215483 · Cited by 303
AMP ‐activated protein kinase: a key regulator of energy balance with many roles in human disease
Grahame Hardie, D. (2014) · Journal of Internal Medicine · doi:10.1111/joim.12268 · Cited by 285
Treyer, A., & Müsch, A. (2013) · Comprehensive Physiology · doi:10.1002/cphy.c120009 · Cited by 252
Somatic LKB1 Mutations Promote Cervical Cancer Progression
Wingo, S. N., Gallardo, T. D., Akbay, E. A., Liang, M.-C., Contreras, C. M., Boren, T., Shimamura, T., Miller, D. S., Sharpless, N. E., Bardeesy, N., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005137 · Cited by 247
The liver kinase B1 is a central regulator of T cell development, activation, and metabolism
MacIver, N. J., Blagih, J., Saucillo, D. C., Tonelli, L., Griss, T., Rathmell, J. C., & Jones, R. G. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100367 · Cited by 235
Zhou, L., Deepa, S. S., Etzler, J. C., Ryu, J., Mao, X., Fang, Q., Liu, D. D., Torres, J. M., Jia, W., Lechleiter, J. D., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.028357 · Cited by 212
Dual Role of Interleukin-6 in Regulating Insulin Sensitivity in Murine Skeletal Muscle
Nieto-Vazquez, I., Fernández-Veledo, S., de Alvaro, C., & Lorenzo, M. (2008) · Diabetes · doi:10.2337/db07-1062 · Cited by 209
RetractedGreen, A. S., Chapuis, N., Trovati Maciel, T., Willems, L., Lambert, M., Arnoult, C., Boyer, O., Bardet, V., Park, S., Foretz, M., et al. (2010) · Blood · doi:10.1182/blood-2010-02-269837 · Cited by 199
AMPK activation: Role in the signaling pathways of neuroinflammation and neurodegeneration
Peixoto, C. A., Oliveira, W. H. D., Araújo, S. M. D. R., & Nunes, A. K. S. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.08.013 · Cited by 196
New Roles for the LKB1-NUAK Pathway in Controlling Myosin Phosphatase Complexes and Cell Adhesion
Zagórska, A., Deak, M., Campbell, D. G., Banerjee, S., Hirano, M., Aizawa, S., Prescott, A. R., & Alessi, D. R. (2010) · Science Signaling · doi:10.1126/scisignal.2000616 · Cited by 193
Self-citationDucommun, S., Deak, M., Sumpton, D., Ford, R. J., Núñez Galindo, A., Kussmann, M., Viollet, B., Steinberg, G. R., Foretz, M., Dayon, L., et al. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.02.008 · Cited by 167
Self-citationLi, F., Han, X., Li, F., Wang, R., Wang, H., Gao, Y., Wang, X., Fang, Z., Zhang, W., Yao, S., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.04.001 · Cited by 169
Thomson, D. M., Porter, B. B., Tall, J. H., Kim, H.-J., Barrow, J. R., & Winder, W. W. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00366.2006 · Cited by 146
Diabetes and Pancreatic Cancer: Chicken or Egg?
Magruder, J. T., Elahi, D., & Andersen, D. K. (2011) · Pancreas · doi:10.1097/mpa.0b013e318209e05d · Cited by 140
Williams, T., Courchet, J., Viollet, B., Brenman, J. E., & Polleux, F. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1013660108 · Cited by 123
LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma
Liu, W., Monahan, K. B., Pfefferle, A. D., Shimamura, T., Sorrentino, J., Chan, K. T., Roadcap, D. W., Ollila, D. W., Thomas, N. E., Castrillon, D. H., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.03.048 · Cited by 127
ESFAHANIAN, N., SHAKIBA, Y., NIKBIN, B., SORAYA, H., MALEKI-DIZAJI, N., GHAZI-KHANSARI, M., & GARJANI, A. (2012) · Molecular Medicine Reports · doi:10.3892/mmr.2012.753 · Cited by 120
LKB1 and AMPK regulate synaptic remodeling in old age
Samuel, M. A., Voinescu, P. E., Lilley, B. N., de Cabo, R., Foretz, M., Viollet, B., Pawlyk, B., Sandberg, M. A., Vavvas, D. G., & Sanes, J. R. (2014) · Nature Neuroscience · doi:10.1038/nn.3772 · Cited by 114
Yamada, E., Bastie, C. C., Koga, H., Wang, Y., Cuervo, A. M., & Pessin, J. E. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.03.014 · Cited by 103
LKB1 is essential for the proliferation of T‐cell progenitors and mature peripheral T cells
Tamás, P., Macintyre, A., Finlay, D., Clarke, R., Feijoo‐Carnero, C., Ashworth, A., & Cantrell, D. (2010) · European Journal of Immunology · doi:10.1002/eji.200939677 · Cited by 94
Kaufman, J. M., Amann, J. M., Park, K., Arasada, R. R., Li, H., Shyr, Y., & Carbone, D. P. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000173 · Cited by 87
Wang, J.-W., Imai, Y., & Lu, B. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.5094-06.2007 · Cited by 80
“LKB1 activity can also be regulated by phosphorylation and by its interaction with molecular chaperone Hsp90 (Alessi et al., 2006).”
BackgroundControlling the master—upstream regulation of the tumor suppressor LKB1
Kullmann, L., & Krahn, M. P. (2018) · Oncogene · doi:10.1038/s41388-018-0145-z · Cited by 75
AMPK signaling in skeletal muscle during exercise: Role of reactive oxygen and nitrogen species
Morales-Alamo, D., & Calbet, J. A. L. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.01.012 · Cited by 72
Estradiol effects on hypothalamic AMPK and BAT thermogenesis: A gateway for obesity treatment?
López, M., & Tena-Sempere, M. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.03.014 · Cited by 70
Lilley, B. N., Pan, Y. A., & Sanes, J. R. (2013) · Neuron · doi:10.1016/j.neuron.2013.05.017 · Cited by 63
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Okon, I. S., Coughlan, K. A., Zhang, C., Moriasi, C., Ding, Y., Song, P., Zhang, W., Li, G., & Zou, M.-H. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75371 · Cited by 52
Oestrogen receptors interact with the α-catalytic subunit of AMP-activated protein kinase
Lipovka, Y., Chen, H., Vagner, J., Price, T. J., Tsao, T.-S., & Konhilas, J. P. (2015) · Bioscience Reports · doi:10.1042/bsr20150074 · Cited by 49
Convergence of IPMK and LKB1-AMPK Signaling Pathways on Metformin Action
Bang, S., Chen, Y., Ahima, R. S., & Kim, S. F. (2014) · Molecular Endocrinology · doi:10.1210/me.2014-1134 · Cited by 45
AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy
Dohmen, M., Krieg, S., Agalaridis, G., Zhu, X., Shehata, S. N., Pfeiffenberger, E., Amelang, J., Bütepage, M., Buerova, E., Pfaff, C. M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14812-0 · Cited by 40
Self-citationColon neoplasia in patients with type 2 diabetes on metformin: A meta-analysis
Rokkas, T., & Portincasa, P. (2016) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2016.05.027 · Cited by 34
Banerjee, S., Zagórska, A., Deak, M., Campbell, D. G., Prescott, A. R., & Alessi, D. R. (2014) · Biochemical Journal · doi:10.1042/bj20140408 · Cited by 32
Self-citationKoenig, M. J., Agana, B. A., Kaufman, J. M., Sharpnack, M. F., Wang, W. Z., Weigel, C., Navarro, F. C. P., Amann, J. M., Cacciato, N., Arasada, R. R., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3199 · Cited by 18
Metadata
- Authors
- Alessi, D. R., Sakamoto, K., & Bayascas, J. R.
- Venue
- Annual Review of Biochemistry
- Publisher
- Annual Reviews
- Published
- 2006-06-01
- Volume
- 75
- Issue
- 1
- Pages
- 137-163
- ISSN
- 0066-4154 (ISSN-L)
- 1545-4509
- OpenAlex
- W2169520827
- Cited by
- 788
- References
- 14
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- closed
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